Sibling Hematopoietic Stem Cell Transplantation Research Articles

Clinical features of 20 cases with Pneumocystis jirovecii pneumonia after allogeneic hematopoietic stem cell transplantation

This study included 20 patients with hematological diseases who developed Pneumocystis jirovecii pneumonia (PJP) after receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) from April 2014 to October 2022 at Peking University People's Hospital. The 20 patients comprised 13 males (65.0% ) and seven females (35.0% ), with a median age of 34 (19-60) years. Eleven cases (55.0% ) of acute myeloid leukemia, four cases (20.0% ) of acute lymphocytic leukemia, two cases (10.0% ) of myelodysplastic syndrome, one case (5.0% ) of chronic myelomonocytic leukemia, one case (5.0% ) of non-Hodgkin lymphoma, and one case (5.0% ) of aplastic anemia were analyzed. Three cases (15.0% ) of HLA-identical sibling hematopoietic stem cell transplantation, three cases (15.0% ) of matched unrelated donor hematopoietic stem cell transplantation, and 14 cases (70.0% ) of haploid hematopoietic stem cell transplantation were identified. The median onset time of PJP was 353 (74-1121) days after transplantation. The clinical symptoms mainly included fever, cough, expectoration, and dyspnea. All patients presented signs of infection based on the CT scan, including bilateral diffuse ground-glass opacities, patchy shadows, and solid nodules. Nine patients (45.0% ) required respiratory support via nasal catheter oxygen inhalation, while seven patients (35.0% ) required ventilator-assisted breathing. Seven (35.0% ) severe infections and 13 (65.0% ) mild to moderate infections were recorded. Moreover, eight patients (40.0% ) were complicated with human cytomegalovirus infection, whereas two patients were complicated with EB virus infection. Furthermore, all 20 patients received treatment with compound sulfamethoxazole (standard dose, 11 cases; low dose, 9 cases). Furthermore, 19 patients survived and one patient died.

The prophylactic application of low-dose rabbit antithymocyte globulin in matched siblings HSCT with high-risk factors for graft-versus-host disease

Relapse and graft-versus-host disease (GVHD) are currently the predominant causes of mortality post allogeneic hematopoietic stem cell transplantation (allo-HSCT). The contentious use of antithymocyte globulin (ATG) for preventing GVHD in matched sibling HSCT scenarios has been a topic of significant debate. A retrospective analysis was conducted on matched sibling HSCT cases with high-risk factors for GVHD in our center from January 2018 to June 2023. Our assessment revealed that the group administered with ATG exhibited a 30 % incidence of acute GVHD (aGVHD), in contrast to 81.8 % in the non-ATG cohort (P = 0.037) among matched sibling HSCT cases with high GVHD risk factors. Furthermore, chronic GVHD (cGVHD) occurred in 20 % of the ATG group and 72.7 % of the non-ATG group (P = 0.03). Notably, the administration of ATG did not significantly impact disease relapse (p = 0.149), infection rates (p = 0.64), granulocyte recovery time (p = 0.15), platelet recovery time (p = 0.12), overall survival (p = 0.889), or disease-free survival time (p = 0.787). The use of rabbit antithymocyte globulin (r-ATG) at a 5 mg/kg dosage demonstrated a notable reduction in aGVHD and cGVHD incidences within sibling matched HSCT cases with high-risk factors for GVHD, without increasing rates of disease recurrence or infections. These findings highlight the potential benefit of using low-dose r-ATG in high-risk of GVHD sibling matched allogeneic HSCTs, although further validation with a larger cohort is necessary.

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in a Child with Myelodysplastic Neoplasm with Complex Karyotype and ETV6 Variant.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelodysplastic neoplasm (MDS). Nevertheless, disease relapse is the main cause of treatment failure. Due to the rarity of childhood MDS (cMDS), there are few studies showing the impact of cytogenetic alterations and genetic variants on outcomes of allo-HSCT, mainly focusing on clonal chromosomal evolution (CCE) during relapse post-transplant. Here, we describe a 3-year-old boy with cMDS-IB, who evolved to MDS/AML. At diagnosis, the patient showed a complex karyotype with chromosomal abnormalities not yet reported together in the same clone, and likely a pathogenic variant in the ETV6 gene. The patient was treated with HLA-matched sibling HSCT, but unfortunately relapsed after HSCT with clonal cytogenetic evolution. This unfavorable outcome suggests that the treatment of pediatric MDS associated with predictive factors of poor prognosis, such as complex karyotype and ETV6 variant remains a challenge.

Efficacy of Triple Prophylaxis for Prevention of Graft-Versus-Host Disease in Matched Sibling Allogeneic Peripheral Blood Hematopoietic Stem Cell Transplantation in Pediatric Patients

BACKGROUND: Graft-versus-host disease (GVHD) continues to compromise the overall success of allogenic hematopoietic stem cell transplantation. It is the most important cause of morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation for malignant disease. In adults, post-transplant cyclophosphamide (Cy-PT) has been shown to be a feasible, economically accessible, and effective strategy to reduce the incidence of GVHD in matched sibling hematopoietic stem cell transplantation in combination with a calcineurin inhibitor plus mycophenolate mofetil (MMF). AIM: Demonstrate the clinical benefit of Cy-PT plus a calcineurin inhibitor combined with MMF for GVHD prophylaxis in HLA-matched, related peripheral blood stem cell transplants in pediatric patients with malignant hematologic neoplasms compared to standard therapy in historical controls. METHODS: A retrospective study was conducted on 22 pediatric patients with malignant hematologic neoplasms who underwent HLA-matched related peripheral blood allogenic stem cell transplantation (alloSCT) between July 2012 and December 2022. A comparison was made between two groups, one with triple prophylaxis using Cy-PT, cyclosporine (CsA), and MMF, and a historical cohort that received standard GVHD prophylaxis based on CsA and methotrexate (MTX). Patients were identified from a hospital registry. Descriptive and inferential statistics will be reported, using SPSS version 25 for analysis. RESULTS: Twenty-two patients received HLA-matched alloSCT from first-degree relatives genotypically identical in HLA-A, HLA-B, and HLA-DRB1 alleles. The demographic characteristics of both groups are summarized in the table. No patient experienced primary graft failure, sinusoidal obstructive syndrome, or hemorrhagic cystitis. Acute GVHD grade II-IV did not develop in patients who received Cy-PT, whereas in the CsA/MTX prophylaxis group, 1 (9%) grade IV patient was observed who died due to this cause before day 100. Two patients (18%) developed Moderate/Severe GVHD in the CsA/MTX group, and 1 (9%) had moderate GVHD in the Cy-PT group. Two-year overall survival was similar between the two groups (Cy-PT 53% and CsA/MTX 67%), as was event-free survival (PTCy 48% vs. CsA/MTX 61%). CONCLUSION: Peripheral blood represents a feasible option in our setting due to rapid graft engraftment, short hospital stays, and low incidence of primary graft failure, but with a higher incidence of GVHD as reported in the literature. We explored the efficacy and safety of triple prophylaxis for HLA-matched alloSCTs from peripheral blood using Cy-PT + CsA + MMF in a small group of patients, with outcomes slightly better than standard prophylaxis. These preliminary results motivate us to continue with this new regimen.

Clonal Dynamics after Haematopoietic Stem Cell Transplantation Using Genome-Wide Somatic Mutations

Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment received by over 40,000 patients/year. Despite being an established treatment for 50 years, fundamental questions remain about the dynamics of long-term stem cell engraftment and immunological reconstitution in humans. How many of the >108 transplanted CD34+ cells contribute to long-term hematopoiesis? How does increasing age of donor and recipient reshape clonal dynamics of HSCT? Are the same HSCs responsible for both myeloid and lymphoid reconstitution? Does HSCT increase mutation rates or clonal evolution? Methods We used spontaneous somatic mutations occurring genome-wide in single hematopoietic stem and progenitor cells (HSPCs) to reconstruct high-resolution lineage trees of the hematopoietic system after HSCT. We analysed blood samples from both the donor (D) and recipient (R) for 10 HLA-matched sibling HSCTs - the duration of time elapsed since transplant ranged from 9 to 31 years, meaning that we could study genuinely long-term reconstitution in the recipient, compared to the unperturbed hematopoiesis in the donor. For each individual (D and R), peripheral blood CD34+ HSPC-derived colonies were grown on methylcellulose medium. Whole genome sequencing was performed on 100-300 colonies per individual, generating a final dataset of 3,413 genomes. Somatic mutations from each colony's founder cell were identified and used to build phylogenies for each D/R pair (Figure). For 7/10 pairs, we then used ultra-deep targeted sequencing to assess clonal contributions in sorted mature D/R cell subsets, including monocytes, B-cells and T-cells. Approximate Bayesian computation was used to estimate numbers of engrafting HSCs. RESULTSIn most cases, 10,000 - 50,000 HSCs engrafted and contributed to long-term reconstitution during HSCT. However, grafts from older donors, or those with lower CD34+ cell doses tended to have lower estimates, some as low as <1,000 cells.Recipients had decreased clonal diversity compared to their donors, equivalent to 8-10 years of additional ageing.We detected 93 individual clones that contributed >1% of the population of at least one mature cell type. Each of these expanded clones was detectable in both the donor and the recipient, confirming that they had originated prior to HSCT.Only ~10% of these expanded clones carried mutations in genes known to contribute to clonal hematopoiesis, suggesting that there are many other genes that can influence stem cell dynamics after HSCT.The sizes of these expanded clones often varied dramatically between donors and recipients, up to 25-fold differences in some instances.The population bottleneck caused by HSCT was not sufficient to explain the differences in clonal composition between recipient and donor, suggesting that there are additional HSCT-specific selective pressures during stem cell harvest, in vitro manipulation, infusion, homing and engraftment.While large proportions of mature myeloid and B-cell populations usually derived from the identified clones, this was not true for T-cell populations. This suggests that following HSCT, T-cells are largely derived from stem cells that do not contribute substantially to myeloid reconstitution.HSPC mutation burdens in recipients were similar to their donors, contradicting previous hypotheses that the proliferative stress of HSCT would lead to excess mutations. CONCLUSION Our findings reveal that tens of thousands of HSCs typically engraft during HSCT, but with significant loss of clonal diversity in recipients compared to their unperturbed donors. HSCT-specific selective pressures shape dynamics of hematopoietic reconstitution in the recipient, with substantial differences in clonal composition between myeloid and T-lymphoid populations. This study shows the power of using somatic mutations as clonal marks for lineage tracing in real-world HSCT in humans, an approach we believe will be a new gold standard for understanding the impact of different stem cell sources and transplant protocols. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Gene Mutation and MRD-Directed Risk Stratification Treatment Improves Long Term Survival of the Patients with AML1-ETO-Positive AML

Purpose: Aim to explore whether risk stratification treatment could improve the disease outcome of the patients with AML1-ETO-positive acute myeloid leukemia (AE-AML) based on gene mutation with next generation sequencing (NGS) and measurable residual disease (MRD) monitoring. Method: A prospective cohort study (NCT02936089) about newly diagnosed AE-AML was performed in five medical centers in China from October 2016 to December 2021. Gene mutations were detected with NGS. MRD monitoring of RUNX1-RUNX1T1 transcript was assessed with quantitative polymerase chain reaction. After two cycles of consolidation, patients received risk stratification treatment as follow. Low risk (LR) group (C-KIT-ASXL1- with main molecular response (MMR)) was recommended to chemotherapy or autologous hematopoietic stem cell transplantation (auto-HSCT). Intermediate risk (IR) group (C-KIT+/ASXL1+ with MMR) was suggested for auto-HSCT or HLA-matched sibling HSCT. High risk (HR) group (C-KIT+ASXL1+ or without MMR) was treated with allogeneic (allo-) HSCT. Result: Totally 198/207 patients including C-KIT-ASXL1- (n=100), C-KIT+/ASXL1+ (n=83) and C-KIT+ASXL1+ (n=15) were available for efficacy analysis in this study. Among the three groups, there was significantly different in the rate of 3-year overall survival (OS) (C-KIT-ASXL1-, 83.1% vs C-KIT+/ASXL1+, 67.4% vs C-KIT+ASXL1+, 23.0%，P<0.001) and cumulative incidence of relapse (CIR) (31.7% vs 33.9% vs 70.4%，P=0.001), while similar in the rate of CR and MRD negative after two cycles of induction (P>0.005). After two cycles of consolidation, the patients were stratified into LR (n=66), IR (n=57) and HR (n=72) groups.The 3-year OS rate (90.5% vs 71.4% vs 57.8%, P<0.001）and CIR (22.9% vs 31.9% vs 48.5%, P<0.001) were apparently different among the three groups. In the three risk groups, the patients following the treatment protocol all had significantly higher 3-year OS (LR 95.0% vs 86.1%，P=0.160; IR 92.3% vs 52.5%, P=0.006; HR 74.3% vs 25.0%, P<0.001) and lower CIR (LR 15.6% vs 27.2%，P=0.048; IR 15.0% vs 48.7%，P=0.006; HR 25.0% vs 84.1%，P<0.001) than those with bias treatment. Conclusion: AE-AML could be further risk stratified based on C-KIT/ASXL1 mutation status and MRD levels after two cycles of consolidation. Gene mutation and MRD-directed risk stratification treatment would improve the long term survival of AE-AML patients.

ALL-503 Lineage Switch Upon Relapse of Acute Leukemia: A Rare Event Which Heralds Poor Clinical Outcomes

Lineage switch in acute leukemias (AL) is a rarely described entity. Several hypotheses have been proposed to explain it, notably the expansion of a coexisting subclone after suppression of the leukemic clone apparent at diagnosis by chemotherapy, alterations brought by chemotherapy upon the original clone, by suppressing differentiation programs, thus inducing a shift in phenotypic expression, or high fate plasticity of the hematopoietic progenitor cells, regulated by microenvironmental signals and transcription factors. We report the case of a patient diagnosed with B-cell acute lymphoblastic leukemia, who relapsed after twelve months, with morphological and immunophenotypic findings consistent with acute monocytic leukemia. An 18-year-old female presented to our clinic with a month-long history of fever, fatigue and menorrhagia. Upon clinical examination, hepatosplenomegaly and unilateral axillary adenopathy were found. Laboratory studies revealed severe pancytopenia with a white blood cell count of 1.6×109/L, hemoglobin value of 2.8 g/dL and platelet count of 30×109/L. Bone marrow (BM) examination showed an 80% lymphoblasts infiltrate, while the immunophenotypic analysis indicated B-cells positive for CD19, cCD79a, CD22, CD24, CD10, CD34, CD38, CD58, with dim expression of CD45, CD20, nuTdT, CD13, CD33, negative for myeloperoxidase (MPO) or markers of monocytic differentiation. No chromosomal or genetic abnormality was detected, including MLL gene rearrangement at 11q23, previously associated with lineage switch in AL. She was treated according to the GRAALL-2003 protocol and achieved complete remission. One year after the primary diagnosis, the BM aspirate showed a hypercellular marrow with 70% blasts, while flow cytometry identified expression of MPO, CD13, CD33 (bright), HLA-DR, CD14, CD15, CD56, CD38. She received chemotherapy with fludarabine, cytarabine and filgrastim, with failure in attaining remission, then followed a clofarabine, cytarabine and idarubicin regimen. At day +23, the BM aspirate showed normocellular marrow with 2-3% blast cells and a sibling hematopoietic stem-cell transplantation was planned, but three weeks later, the peripheral blood smear showed 43% blasts with monocytoid morphology. She is currently undergoing treatment with azacytidine and venetoclax. Despite tremendous advancements in the understanding of AL, many questions regarding the molecular mechanisms driving lineage switch need to be addressed. This rare phenomenon is associated with therapy resistance and poor clinical outcomes.

Comparable Outcomes in Acquired Severe Aplastic Anemia Patients With Haploidentical Donor or Matched Related Donor Transplantation: A Retrospective Single-Center Experience.

Clinical data of patients with severe aplastic anemia (SAA) were retrospectively analyzed to evaluate the outcomes of haploidentical hematopoietic stem cell transplantation (HID-HSCT) with matched related sibling hematopoietic stem cell transplantation (MSD-HSCT) in complications and survivals. Thirty consecutive patients were enrolled in the study with a median follow-up of 50 months (range 4, 141), and the median age of the patients was 21 years (range 3, 49). All the patients achieved myeloid engraftment in the two cohorts. The cumulative incidences of platelet engraftment were 95.5 and 100% in HID cohort and MSD cohort, respectively. The median time for neutrophil and platelet recovery was 11 (range 9, 19) and 15 (range 10, 25) days in HID cohort, and 12 (range 10, 19) and 14 (range 8, 25) days in MSD cohort. The cumulative incidences of grade II–IV and grade III–IV acute graft vs. host disease (aGvHD) in HID cohort and in MSD cohort were 18.9 vs. 14.3% (p = 0.77) and 10.5 vs. 0% (p = 0.42), respectively. The cumulative incidences of chronic graft vs. host disease (cGvHD) was 22.7% in HID cohort and 25.5% in MSD cohort (p = 0.868). The 5-year overall survival (OS) rates and 5-year failure-free survival (FFS) rates in HID cohort and MSD cohort were 85.1 vs. 87.5% (p = 0.858), 80.3 vs. 87.5% (p = 0.635), respectively. The median time to achieve engraftment, cumulative incidence of aGvHD and cGvHD, and the 5-year OS and FFS rates were not significantly different between the two cohorts. We suggest that HID-HSCT might be a safety and effective option for SAA patients without a matched donor.

Nonmyeloablative HLA-Identical Sibling Donor Transplantation for Children and Young Adults with Sickle Cell Disease: Interim Results of the SUN Multicenter Phase II Trial

Background: HLA-identical sibling hematopoietic stem cell transplant (HSCT) using myeloablative chemotherapy conditioning is a proven cure for sickle cell disease (SCD), but is associated with serious short and long-term toxicities. Additionally graft versus host disease (GVHD) can complicate care post-HSCT and contribute to mortality. Given these concerns many pediatric hematologists and families are reluctant to pursue HSCT for SCD. Nonmyeloablative HSCT resulting in stable mixed chimerism has been demonstrated to abrogate the SCD phenotype in adults. Data on outcomes of this approach to decrease toxicities and achieve cure in children remains scarce.Objective: To evaluate event-free survival (EFS), toxicity, health-related quality of life (HRQL), and transfusion burden among pediatric patients with SCD using a chemotherapy-free nonmyeloablative regimen.Methods/design: Children and young adults with SCD were prospectively enrolled in the Sickle transplant Using a Nonmyeloablative approach (SUN) multicenter clinical trial (NCT03587272). Six Sickle Cell Transplant Advocacy and Research Alliance (STAR) sites in the United States and Canada enrolled patients. The conditioning regimen consisted of alemtuzumab IV (0.03mg/kg on Day -7, 0.1mg/kg on Day -6, 0.3mg/kg on Days -5 to -3), low-dose total body irradiation with gonadal shielding (300 cGY on day -2), peripheral blood stem cells from an HLA-identical sibling, and sirolimus for at least one year. Baseline HRQL was compared with scores at day +30 and day +100 post-HSCT using the PedsQL and PROMIS measures. EFS was defined by any of the following events: death, graft failure (myeloid donor chimerism <10%), or GVHD.Results: All 30 of the patients planned for the primary endpoint of EFS have been enrolled. As of 7/20/2021, 24 patients are greater than 100 days post-HSCT with a median follow-up of 365 days (range 189-1105). The median age of this group at time of transplant was 13.5 years (range 2-22). All patients had neutrophil recovery (ANC >500/ul x 3 days) at a median of 21.5 days (range 0-29). Eleven patients (46%) did not require any platelet transfusions. Median transplant hospitalization was 16.5 days (range 14-43). Seven patients (29%) were again hospitalized (median 4 days, range 1-26). Three patients had secondary graft rejection at Day +71, +91, and +92 with no major complications and autologous recovery resulting in an EFS of 87.5% (Figure 1). Three additional patients have stable low donor chimerism (myeloid chimerism 11%, 38%, and 47%). The remaining 18 patients (75%) are disease-free and have robust donor engraftment (72-100% myeloid chimerism). Nine of these patients are >1 year post-HSCT and off sirolimus. Overall survival is 100% with no acute or chronic GVHD. Figure 2 shows total PedsQL scores during the peri-transplant time period. The median change in day +30 scores compared to baseline was 0 (IQR -7, +10), p=0.66. The median change in day +100 scores compared to baseline was +5 (IQR 0, +10), p=0.02.Conclusions: Outcomes of pediatric nonmyeloablative HLA-identical sibling HSCT for SCD appear similar to the larger adult experience with a GVHD-free, rejection-free survival of >80%. Importantly, patients have no worsening of their quality of life in the first month post-HSCT and already an improvement at day +100, suggesting that the short-term toxicities experienced by patients transplanted with this regimen are minimal. The majority of patients achieve disease resolution with no GVHD, but graft failure incidence appears higher than with myeloablative HSCT. Given the low intensity of this approach, a reasonable strategy may be to reserve myeloablation for a second transplant in the minority of patients who experience graft failure. [Display omitted] DisclosuresRangarajan: Medexus (Treosulfan): Consultancy, Honoraria. Guilcher: BlueBirdBio: Research Funding; Project Sickle Cure Study: Other: Principal Investigator, Research Funding. OffLabel Disclosure:alemtuzumab and sirolimus were used off-label as part of the studied transplant regimen

Nonmyeloablative Transplant for Sickle Cell Disease Does Not Lead to Kidney Dysfunction Post-HSCT

Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for patients with sickle cell disease (SCD). Though HSCT can reverse the SCD phenotype, both acute kidney injury (AKI) and chronic kidney disease (CKD) have been associated with HSCT. SCD alters renal function thus the impact of HSCT on renal function in SCD patients is a critical area of exploration. Here, we report the effect of HSCT on renal function in people with SCD.This study analyzes data from 195 patients who received HLA-matched sibling or haploidentical HSCT for SCD at Imperial College London (ICL), National Institutes of Health (NIH), and University of Illinois Chicago (UIC). The former is a pediatric cohort and all sites employed a nonmyeloablative conditioning. Patients' renal function was assessed at baseline and annually thereafter for up to 3-years.We examined the prevalence of CKD before and after HSCT, estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) trends after HSCT, and the incidence of AKI within 100 days of HSCT. We defined and staged AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria; we calculated eGFR with the CKD- epidemiology collaboration (CKD-EPI) equation for adults and Bedside Schwartz for children.The median eGFR declined annually but remained within the normal range throughout the follow-up period: the baseline median eGFR was 138 ml/min/1.73m 2 and declined by 7 in the first year of follow-up and by additional decreases of 5 and 3.6 ml/min/1.73m 2 in subsequent years (p-values of 0.07, 0.0002, and 0.0002 for years 1, 2, and 3 for comparison to baseline from regression model of eGFR). No differences in eGFR were seen for covariates in the model: haploidentical vs. matched sibling, engraftment status, gender, or site. The downward eGFR trend may represent an improvement in renal function toward normal as hyperfiltration (eGFR ≥150 ml/min/1.73m 2) was present in 28% of patients at baseline and steadily declined to 7% by 3 years post-HSCT. There was a corresponding increase in patients with normal eGFR (60-149 ml/min/1.73m 2) from 59% at baseline to 88% at 3 years post-HSCT.Among the ICL and NIH cohorts (UIC excluded due to use of a different AKI determination strategy), 58% of patients developed AKI in the early post-HSCT period. 67% of AKI cases were mild, stage 1; 25% were moderate, stage 2; and 8% were severe, stage 3 AKI.This study demonstrates that HSCT in patients with SCD is associated with a transient increase in UACR but not associated with a significant increase in CKD prevalence by 3-years post-HSCT. The stability of UACR compared to baseline by the 3-year time point suggests that even more mild renal damage may stabilize after HSCT. While there is a substantial decline in eGFR from baseline to each annual follow-up, the proportion of patients whose eGFR was in the normal range increased as the prevalence of hyperfiltration decreased. Finally, while AKI occurred in more than half the patients in our cohort, the preponderance developed only mild AKI. Therefore, our data indicate that nonmyeloablative HSCT for SCD does not lead to significant kidney dysfunction post-HSCT. DisclosuresSaraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Diamantidis: United Health Group: Consultancy.

Reduced-Intensity Conditioning Is Successful in Matched Sibling Bone Marrow Transplantation As a Cure for Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is the most common genetic disease in this country, affecting 1 in every 72,000 individuals in the United States, with sickle cell trait found in 1 in 12 African-Americans. Without curative therapy, disease related mortality is as high as 14% in adolescents and young adults, with a decreased life expectancy compared to individuals without SCD. Hematopoietic stem cell transplantation (HSCT) is the only established cure, and matched sibling HCST have been performed for 30 years with great success. Unfortunately, only about 14% of SCD patients have a matched sibling. Most SCD HSCT protocols use myeloablative (MAB) conditioning in matched sibling transplants with average overall survival (OS) and disease-free survival (DFS) of 90% and 95% respectively, but with potential long-term complications including infertility following its use. Reduced Intensity Conditioning (RIC) has been used in young patients with malignancies with better tolerance and fewer complications. In an attempt to minimize risk and maximize cure, our study examined the use of a RIC regimen for both matched sibling and alternative donor HSCT in SCD patients ages 2-30.Primary Objective: To determine DFS after matched sibling or unrelated transplant after a conditioning regimen consisting of Alemtuzumab, Fludarabine, and Melphalan.Methods: The Institutional Review Board of Hackensack University Medical Center approved this study for human subjects. Strict stopping rules were established for graft rejection and death. Eligibility criteria included a diagnosis of SCD for patients receiving matched sibling donor HSCTs, but did not require any specific complications. For alternative donor HSCTs, eligibility criteria included specific complications associated with severe disease, and required a 9-10/10 unrelated donor or 5-6/6 UCB in the donor registry. All patients underwent partial exchange transfusions for a goal of HbS <45% at the start of conditioning. Conditioning initially consisted of Alemtuzumab beginning on d -22 followed by Fludarabine and Melphalan. However, Alemtuzumab was moved up to d -16 after 7 patients were enrolled to reduce graft vs host disease (GVHD). Due to increasing host chimerisms in 3 patients, the Alemtuzumab was moved back to d-22 after an additional 7 patients were enrolled. Post-HSCT, GVHD prophylaxis consisted of Tacrolimus (trough goal of 10-20) through d+100, mycophenolate mofetil through d+45, and steroids (for unrelated donors) through d+28. Patients were monitored closely for signs of infection with weekly PCRs for adenovirus, CMV and EBV. Donor chimerism by STR and HbS percentages by electropheresis were assessed at d+30, d+60, d+100, 1 year and 2 years post HSCT.Results: A total of 20 patients (17 related, 3 unrelated) were enrolled, with age at transplant ranging from 2.25 to 25.4 years. 3 patients were initially consented to the related arm, but then were found to be ineligible due to organ dysfunction or compliance issues. OS and DFS in patients with related donors were 100% and 94%, with one patient suffering secondary graft rejection. The OS and DFS in patients with unrelated donors were 66% and 33%, with one patient dying from GVHD complications and a second patient suffering secondary graft rejection. The unrelated patient with graft failure did receive a second HSCT off study, but died due to GVHD complications. Mean neutrophil engraftment occurred at d+14 and d+11 and platelet engraftment occurred at d+40 and d+26 for related and unrelated donors, respectively. The incidence of acute GVHD stage II-IV was 35% (7/20 patients), occurring in 6/17 (35%) related and 1/3 (33%) unrelated BMT patients. Chronic GVHD was noted in 20% of patients (4/20), occurring in 3/17 (18%) related and 1/3 (33%) unrelated BMT patients. Chimerisms ranged from 20-100% with HbS% of 0-62%.Conclusions : Our results show that a RIC regimen is well-tolerated with successful engraftment in patients undergoing matched sibling HSCT. However, the complications of GVHD & graft rejection in unrelated transplants greatly affected the DFS. The results are promising for continued use of this regimen for related HSCT even in SCD patients with minimal complications, but other alternatives need to be developed for unrelated HSCT. DisclosuresNo relevant conflicts of interest to declare.

Pilot Study of Safety and Efficacy of Chidamide in Allogenic Peripheral Hematopoietic Stem Cell Transplantation: Better Disease Control and Positively Lower Graft Versus Host Disease

IntroductionThe combination of busulfan (Bu) and fludarabine (Flu) is an effective and well-tolerated hematopoietic stem cell transplantation (HCT) conditioning regimen for patients with acute leukemia. However, relapse remains the main reason for treatment failure. Increasing intensity of conditioning therapy leads to not only better control of disease, but more treatment related mortality including graft versus host disease (GVHD). Song and Partow demonstrated that introducing histone deacetylase inhibitor (HDACi) vorinostat into busulfan/fludarabine/clofarabine (Bu/Flu/Clo) could augment disease control in vitro and in vivo, without increasing toxicity. Pavan and Choi showed vorinostat decrease GHVD while preserving graft versus leukmia effect. We conducted a clinical trial to evaluate the role of a selective HDACi chidamide in allogenic HCT.MethodsChidamide was given orally twice weekly at dose of 20 mg from day -7 to 2 weeks post transplantation. Busulfan was administered intravenously at fixed dose of 3.2 mg/kg for 4 days from day -6 to -3. Fludarabine and cytarabine were given intravenously at dose of 30 mg/m2 and 1g//m2 respectively for 5 days from day -6 to -2. GVHD prophylaxis was based on post-transplantation cyclophosphamide (50 mg/kg on day +3, +4) and cyclosporine started from day +5. The presence of minimal residual disease (MRD) was determined by multi-parameter flow cytometry.ResultsForty patients (24 AML, 6 MDS, 10 ALL) with median age 41 years (range 16-60) received an allogeneic matched sibling (n=34) or unrelated donor (n=6) HCT in CR1 (n=15), CR2 (n=6), with residual disease (n=10), or with active disease (n=9). Seventeen patients had adverse risk karyotype according to European LeukemiaNet risk stratification. Median time to ANC > 0.5 x 109/L and platelets > 20 x 109/L were 16 (range 9-36) and 18 days (11-44), respectively. Short-term (before recovery of ANC and platelets) adverse events included neutropenic fever (80%), reversible grade 2 elevation of liver enzyme (42.5%), and grade 2 mucositis (27.5%). Median follow-up time of the whole cohort was 11.5 months (3-24.7). All patients achieved CR and clearance of MRD by day +30 after HCT. All patients achieved 100% donor chimerism at 30 days following HCT. The incidence of grades II-IV and grade III-IV acute GVHD is 11% and 5% respectively. Only one patient died of aGVHD. Chronic extensive GVHD among 38 evaluable patients is 9%. Median follow-up time of the whole cohort is 11.5 month (3-24.7). Estimated progression free survival and overall survival at 1 year are 75% and 84.6% respectively (Figure1-A). Patients with MRD have inferior survival compere with patients without MRD (81.2% vs 68% p=0.336) (Figure 1-B).ConclusionShort-term results indicate introducing chidamide into allogeneic HCT could lead to better control of disease and possible lower GVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk Factors and Outcomes According to Age at Transplant with an HLA Identical Sibling for Sickle Cell Disease

Background: Hematopoietic stem cell transplant (HSCT) from an HLA identical (HLAid) sibling donor is a well-established curative therapy for sickle cell disease (SCD). However, the ideal age to perform HSCT in SCD patients remains controversial. We report the outcomes after HLAid sibling HSCT for SCD according to patient's age at the time of HSCT as well as their pre-transplant characteristics.Methods: We retrospectively analyzed 727 HLAid sibling HSCTs performed between 1986 and 2015 in 98 EBMT centres. Patients were divided in three groups according to their age at the time of HSCT: <5 year-old (n=176): group 1, 6-15 year-old (n=431): group 2 and >15 years old (n=120): group 3. Primary endpoint was probability of 3-year overall survival (OS) according to age group.Results: Median follow-up was 46 (range: 0.5-346) months. Median age at HSCT was 4 (range: 0.9-5) years in patients <5 years, 10 (range: 6-14) years in patients 6-15 years and 17 (range: 15-39) years in patients >15 years. Gender distribution did not significantly differ among the three groups. The most common SCD genotype was homozygous (SS) in the three groups (95% vs 92% vs 84%, p=0.004). Positive cytomegalovirus (CMV) serology was less frequent in group 1 (63% vs 79% vs 83%, p<0.001. Also, patients in group 1 were less treated with hydroxyurea (37% vs 60% vs 77%, p<0.001), received less than 20 red blood cell units transfusions (32% vs 43% vs 58%, p=0.002) and presented less than 3 SCD complications before HSCT (11% vs 19% vs 39%, p<0.001). For all age groups, vaso occlusive crisis (VOC), acute chest syndrome (ACS) and cerebral vasculopathy were the most reported SCD complications, and the main indications for HSCT were VOC, cerebral vasculopathy, ACS and nephropathy.The proportion of patients with Karnofsky performance status (KPS) <80 did not differ between groups. Graft source distribution was bone marrow (BM) in 74%, cord blood (CB) in 23% and peripheral blood (PBSC) in 3% of cases in group 1; BM in 85%, CB in 11% and PBSC in 4% of cases in the group 2; BM in 79%, CB in 1% and PBSC in 20% of cases in group 3 (p<0.001). Conditioning regimen was myeloablative in 97% of cases in group 1, 96% in group 2 and 83% in group 3 (p<0.001), and included in vivo T cell depletion, mostly antithymocyte globulin (ATG), in 74%, 86% and 90% of the cases, respectively (p<0.001). In all groups, graft versus host disease (GvHD) prophylaxis was mainly cyclosporine- A with methotrexate±mycophenolate mofetil. ABO and gender match between donor and recipient did not significantly vary among groups.Neutrophil engraftment at day +60 was 96%+1 in the first group, 98%+1 in the second group and 95%+2 in the third group (p=0.009). Four patients in group 1, 10 patients in group 2 and 6 patients in group 3 had primary graft failure. The first group experienced less acute GvHD (aGvHD) within 100 days after HSCT (9%+2 vs 18%+2 vs 17%+4, p=0.022) and less chronic GvHD (cGvHD) within 3 years after HSCT (9%+2 vs 12%+2 vs 20%+4, p=0.006). Three-year OS was significantly better in group 1 (99%+1 vs 95%+1 vs 88%+3, p<0.001) as well as 3-year event free survival (EFS) (96%+2 vs 92%+1 vs 84%+4, p=0.001). In a subset of patients with available chimerism data (n=405), in group 1 and group 2 65% were full donor, 32% mixed chimeras and 3% autologous reconstitution whereas in group 3 46% were full donor, 49% mixed chimeras and 5% autologous reconstitution. A univariate risk factor survival analysis was performed for group 3 (only group with sufficient events for analysis), but no patient, donor or HSCT risk factors influencing OS were identified.Conclusion: Patients transplanted at a young age have a better 3-year OS and 3-year EFS, with lower incidence of aGvHD and cGvHD. These findings outline the importance of early referral to HSCT for SCD patients. Strategies to further evaluate pre HSCT, HSCT and donor factors that may influence survival and adverse outcomes could help improve HSCT results. Disclosuresde la Fuente:Jazz Pharmaceuticals: Honoraria; bluebird bio: Consultancy; HCA: Consultancy. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

Transplantation for Congenital Sideroblastic Anaemia Is Feasible and Offers Outcomes Comparable to Other Transfusion Dependent Anaemias. a Joint Retrospective Study of the Paediatric Diseases and Severe Aplastic Anaemia Working Parties (PDWP/SAAWP) of EBMT

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment &amp;gt;20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Renal Function Is Preserved after Hematopoietic Stem Cell Transplantation for Sickle Cell Disease

Chronic kidney disease (CKD) is a common complication and a significant contributor to morbidity and mortality for patients with sickle cell disease (SCD). Hematopoietic stem cell transplantation (HSCT) is a curative strategy for SCD and potentially life-saving therapy. Though HSCT can reverse the SCD phenotype, acute and chronic kidney dysfunction may be an unintended consequence. The incidence of acute kidney injury (AKI) and the effect of different HSCT regimens on progression or amelioration of CKD in adults with SCD have not previously been reported. This cohort study analyzes prospectively collected data from 106 patients transplanted for SCD at the National Institutes of Health (NIH) Clinical Center, including HLA-matched sibling (N=71) and haploidentical HSCT (N=26) where nonmyeloablative conditioning was given, as well as gene therapy (N=9), where a myeloablative regimen was employed. Patients' renal function was assessed at baseline and annually thereafter for up to 3-years. We sought to define 1) the prevalence of CKD before and after HSCT 2) the incidence of CKD after HSCT 3) estimated glomerular filtration rate (eGFR) trends after HSCT 4) urine albumin to creatinine ratio (UACR) change after HSCT and 5) the incidence of AKI within 100 days of HSCT. We defined and staged AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria (stage 1: 1.5-1.9 times baseline serum creatinine increase or ≥0.3 mg/dl increase; stage 2: 2-2.9 times baseline; stage 3: 3 times baseline, increase in creatinine to ≥4.0 mg/dl, or initiation of renal replacement therapy). The baseline prevalence of CKD was 6% when defined conservatively (eGFR &amp;lt;60 ml/min/1.73m2); this prevalence did not change significantly post-HSCT. When using a more comprehensive definition of CKD (urine albumin to creatinine ratio (UACR) ≥30 mg/g OR eGFR &amp;lt;60 ml/min/1.73m2), 48% had CKD at baseline, 62% at 1 year, 55% at 2 years, and 55% at 3 years (with p=0.02, 0.26, 0.54 for longitudinal model comparing post-HCST prevalence to baseline). The incidence of CKD any time after HSCT was 1% and 11% according to each of these CKD definitions, respectively. 25% of participants had follow-up of ≤2 years, median follow-up was 3 years. The median eGFR remained within the normal range throughout the follow-up period but declined annually: the baseline median eGFR was 139.7 ml/min/1.73m2 and declined by 7.6, 11.6, and 20.9 ml/min/1.73m2 each year post-HSCT (p&amp;lt;0.0001). In an adjusted regression analysis, there was no association of gender, engraftment status, transplant regimen, or conditioning agent- specifically use of pentostatin, total body irradiation, or post-transplant cyclophosphamide- with worsening eGFR (p&amp;gt;0.05 for each variable). This eGFR trend represents an improvement in renal function toward the normal range: there was a statistically significant decrease in hyperfiltration (eGFR ≥150 ml/min/1.73m2), which was present in 34% patients at baseline but steadily declined to 12% by 3 years post-HSCT (p = 0.0006 for adjusted longitudinal model). There was a corresponding increase in patients with normal eGFR (60-149 ml/min/1.73m2) from 60% at baseline to 80% at 3 years post-HSCT. UACR showed an increase in the year following transplant that subsequently dissipated. Median UACR at baseline was 24.3 mg/g with annual follow-up median values of 62.2, 38.9 and 36.2 mg/g (p-values of 0.007, 0.41, and 0.69 for comparison to baseline from regression model of log transformed UACR). In our cohort, 58% of patients experienced AKI in the first 100 days post-HSCT; which is consistent with previous data. 77% of those were mild, stage 1; 13% were moderate, stage 2; and 10% were severe, stage 3 AKI. This study demonstrates that HSCT in patients with SCD is not associated with a significant increase in CKD incidence or prevalence at 2 and 3 years post-HSCT. While there is a substantial decline in eGFR from baseline to each annual follow-up, the proportion of patients whose eGFR was in the normal range increased and the prevalence of hyperfiltration decreased. The stability of UACR after an initial increase at the 1-year time point further suggests that even more mild renal damage may stabilize after transplant. Finally, AKI occurred in over half of the patients in our cohort, though the preponderance developed mild AKI. Disclosures Diamantidis: United Health Group: Membership on an entity's Board of Directors or advisory committees.

“Real World” Australian Experience of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Adults with Severe Aplastic Anaemia.

Acquired Severe Aplastic Anaemia (SAA) is a rare bone marrow failure syndrome, for which allogeneic haematopoietic stem cell transplant (HSCT) is a proven curative therapy. Despite excellent outcomes for matched sibling SAA recipients in terms of engraftment and survival, HSCT remains highly challenging in older matched-unrelated-donor (MUD) recipients, due to increased non-relapse mortality (NRM) from causes such as graft versus host disease (GVHD), organ failure and infection. We sought to evaluate our local HSCT outcomes for SAA, determine factors that predict for inferior outcomes, and benchmark local outcomes against international cohorts. To define outcomes for sibling and MUD HSCT in adults ≥17 years of age with SAA at a single Australian institution between 2002 and 2018 and compare these outcomes to internationally published cohorts. The primary outcome was 1-year overall survival (OS). Secondary outcomes included the incidences of engraftment, response, secondary graft failure, GVHD, and moderate to severe organ dysfunction. All 21 patients comprising 10 sibling and 11 MUD HSCTs, with a median age of 30 (range 17-64), received bone marrow grafts. At a median follow up of 3.5 years, 17 (81%) of 21 patients remained alive and in remission from SAA. 1-year OS, non-relapse mortality (NRM), and GVHD incidence were 85%, 15%, and 48% respectively. Two patients died prior to engraftment at Day+27 and Day+33. When comparing sibling and MUD HSCT recipients, incidences of survival, engraftment and post-HSCT complications were similar; however, MUD HSCT survivors experienced a higher incidence of chronic GVHD (67% vs. 11%; p=0.04). Age &gt;40 years, AKI by Day+28, infection by Day+100 and deviation from intended GVHD prophylaxis predicted for worse OS. Our outcomes following HSCT for SAA are comparable to international cohorts with age &gt;40 years, early onset infection, AKI and deviation from intended GVHD prophylaxis protocol negatively impacting OS. Further research is warranted to optimise MUD HSCT conditioning and GVHD prophylaxis protocols for SAA, particularly in older patients.

Analysis of Factors Influencing Overall Survival of MDS Patients Transplanted with HSCs

To analyze the effect of clinical features, routine laboratory examination and related gene mutation on the OS of patients with myelodysplastic syndrome (MDS) after hematopoietic stem cell transplantation (HSCT). 121 patients diagnosed as MDS and underwent hematopoietic stem cell transplantation in the First Affiliated Hospital of Soochow University from October 2013 to August 2018 were selected. Basic information of the patients was collected, and blood cells, bone marrow blasts at initial diagnosis, chromosomal karyotypes and gene mutations of the patients were detected.The effect of different factors on overall survival (OS) was analyzed by statistical method. Kaplan-Meier univariate analysis shows that OS was significanly different among different age groups. The 3-year OS rate of patients aged 0-29 years was (83.3±7.7) %, the 3-year OS rate in patients aged 30-49 years was (58.1±7.7 %), and the 3-year OS rate of patients aged 50-69 years was (31.0±22.6) %, which was statistically different (P＜0.05) between different groups. There were also significant differences in OS among patients with different transplantation types. 3-year OS rate: HLA-matched sibling HSCT＞unrelated HLA-matched HSCT＞haploidentical HSCT＞micro HSCT. The OS rate of patients with bone marrow blasts≥10% seems lower than blasts＜10%, but there was no statistical difference.The 3-year OS rate of patients with chromosomal karyotype complex abnormality was (47.7±11.5) %, and that of patients without complex abnormality was (80±4.2) % which was statistical difference (P＜0.05). Patients with DNMT3A, NRAS, TP53 and GATA2 mutations had shorter OS time compared with patients without mutation of these genes, which shows statistically significant (P＜0.05). COX multivariate analysis showed that age, chromosome karyotype, DNMT3A, TET2, GATA2 and NRAS were the independent factors influencing OS of patients after HSCT, with statistically significant difference. age of patients, donor selection of HSCT, chromosome karyotype, DNMT3A, NRAS, TP53, GATA2 and TET2 gene mutations are all independent factors affecting the OS of patients after HSCT. Therefore, the assessment of the OS of MDS patients with transplantation requires comprehensive consideration.

The impact of pre-existing HLA and red blood cell antibodies on transfusion support and engraftment in sickle cell disease after nonmyeloablative hematopoietic stem cell transplantation from HLA-matched sibling donors: A prospective, single-center, observational study.

BackgroundHematopoietic stem cell transplantation (HSCT) is curative for patients with sickle cell disease (SCD). Prior to HSCT, patients with SCD commonly receive RBC transfusions with some becoming RBC or HLA alloimmunized. This alloimmunization may impact post-HSCT transfusion requirements and donor engraftment.MethodsThe study population included patients with SCD transplanted on a single-center nonmyeloablative, HLA-matched sibling HSCT trial at the National Heart, Lung, and Blood Institute (NHLBI) who had a pre-HSCT sample available for HLA class I antibody testing. We evaluated transfusion requirements and engraftment outcomes comparing patients with and without pre-existing HLA and RBC antibodies.FindingsOf 36 patients studied, 10 (28%) had HLA class I antibodies and 11 (31%) had a history of RBC alloantibodies. Up to day +45 post-HSCT, patients with HLA antibodies received more platelet transfusions (median 2.5 vs 1, p = 0.042) and those with RBC alloantibodies received more RBC units (median 7 vs 4, p = 0.0059) compared to respective non-alloimmunized patients. HLA alloimmunization was not associated with neutrophil engraftment, donor chimerism, or graft rejection. However, RBC alloimmunization correlated with a decreased donor T cell chimerism at 1 year (median 24% vs 55%, p = 0.035).InterpretationPre-existing HLA and RBC alloantibodies are clinically significant for patients undergoing HLA-matched nonmyeloablative HSCT. Testing for both HLA and RBC antibodies is important to help estimate transfusion needs peri‑HSCT. The association of lower donor T cell chimerism and pre-existing RBC alloantibodies needs further investigation.FundingNIH Clinical Center and NHLBI Intramural Research Program (Z99 CL999999, HL006007–11) and the Thrasher Research Fund.

Clinical Analysis of Allogeneic Hematopoietic Stem Cell Transplantation for Treatment of 12 Patients with Acute Leukemia in Tropical Area

To analyze the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for treatment of acute leukemia in the tropical area. Twelve acute leukemia patients who were underwent allo-HSCT from April 2013 to November 2018 in Hainan Hospital of Chinese PLA General Hospital were selected, including 5 cases of acute lymphoblastic leukemia (ALL) and 7 case of acute myeloid leukemia (AML). Three cases received HLA matched sibling hematopoietic stem cell transplantation, 8 cases received haploidentical hematopoietic stem cell transplantation, 1 cases received partially mismatched unrelated hematopoietic stem cell transplantation. Pretreatment regimen: 9 cases received modified BU/CY+ATG pretreatment regimen, 3 cases received BU/CY pretreatment regimen. Graft-versus-host disease (GVHD) prevention regimen: all patients received cyclosporine A, mycophenolate mofetil combined with short-term methotrexate regimen. The clinical efficacy of allo-HSCT in treatment of acute leukemia in the tropical area was analyzed by detecting hematopoietic reconstitution, GVHD, infection, relapse and survival after transplantation. All the 12 patients achieved granulocyte reconstruction and megakaryocyte reconstruction. The median time of granulocyte reconstruction was 11.5 (6-14) days, and the median time of megakaryocytic reconstruction was 12.5 (10-22) days. Within 100 days after transplantation, the acute GVHD occurved in 8 cases, including 6 cases of Ⅱ-Ⅳ degree acute GVHD and 2 cases of Ⅲ-Ⅳ degree acute GVHD, 11 cases survived more than 100 days after transplantation, and the chronic GVHD occurred in 1 case, which was mildly limited. Pulmonary infection occurred in 7 cases, cytomegaloviremia occurred in 6 cases, EB viremia occurred in 6 cases, and hemorrhagic cystitis occurred in 5 cases. 2 cases relapsed and eventually died, and the remaining 10 patients survived without disease until the date of follow-up. The median follow-up time was 4 (1-68) months, 83.3% (10/12) survived without disease, and 16.7% (2/12) relapsed. Allo-HSCT is an effective method for the treatment of acute leukemia in adults. Leukemia patients should be transplanted as soon as possible after remission. The incidence of pulmonary fungal infection in transplanted patients in tropics is high, therefore the prevention and treatment of fungal infection should be strengthened.

Impact of donor KIRs and recipient KIR/HLA class I combinations on GVHD in patients with acute leukemia after HLA-matched sibling HSCT

In addition to T cells, NK cells can also participate in the outcome of hematopoietic stem cell transplantation (HSCT) mainly through the interaction between donor killer cell immunoglobulin-like receptors (KIRs) and recipient human leukocyte antigen (HLA) class I molecules. There is a risk of GVHD other than leukemia relapse after allogeneic HSCT that activation of donor NK cells in the absence of appropriate inhibitory ligands will be one of the reasons. To investigate the impact of donor KIRs and recipient KIR/HLA class I combinations on GVHD and leukemia relapse in patients with acute leukemia after HSCT, 100 patients with acute leukemia who received HSCT from their HLA-matched siblings were included in this study. Genotypes of 16 KIR genes and two 2DS4 variants (full length and deleted alleles), along with HLA-A/B genotypes, were determined by PCR-SSP. HLA-C genotyping was done with the SSO-Luminex method. Chimerism analysis was done using 16 short tandem repeats (STRs) to detect early leukemia relapse. Acute (a)GVHD occurred in 38 patients, and 16 of them died during the study. None of the recipients showed any sign of leukemia relapse after HSCT. Full donor chimerism was observed in all tested patients during the first year after HSCT. Our results also indicated an increased risk of aGVHD in AA recipients with the C2/Cx, Bw4+ (or A-Bw4+) or HLA-A3−/A11− genotypes who received HSCT from Bx donors. Our results showed that donor selection based on donor-recipient KIR genotypes and recipient HLA class I status can improve the outcome of HSCT.