Transplantation For Severe Aplastic Anemia Research Articles

Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT

AbstractSelecting the most suitable alternative donor becomes challenging in severe aplastic anemia (SAA) when a matched sibling donor (MSD) is unavailable. We compared outcomes in patients with SAA undergoing stem cell transplantation (SCT) from matched unrelated donors (MUD) (n = 1106), mismatched unrelated donors (MMUD) (n = 340), and haploidentical donors (Haplo) (n = 206) registered in the European Society for Blood and Marrow Transplantation database (2012-2021). For Haplo SCT, only those receiving posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis were included. Median age was 20 years, and the median time from diagnosis to transplantation 8.7 months. Compared with MUD, MMUD (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.52-5.6) and Haplo (HR, 5.15; 95% CI, 2.5-10.58) showed significantly higher risks of primary graft failure. MUD had lower rates of acute GVHD compared with MMUD and Haplo (grade 2-4: 13%, 22%, and 19%, respectively; P < .001; grade 3-4: 5%, 9%, and 7%, respectively; P = .028). The 3-year nonrelapse mortality rate was 14% for MUD, 19% for MMUD, and 27% for Haplo (P < .001), whereas overall survival and GVHD and relapse-free survival (GRFS) rates were 81% and 73% for MUD, 74% and 65% for MMUD, and 63% and 54% for Haplo, respectively (P < .001). In addition to donor type, multivariable analysis identified other factors associated with GRFS such as patient age, performance status, and interval between diagnosis and transplantation. For patients with SAA lacking an MSD, our findings support MUDs as the preferable alternative donor option. However, selecting between an MMUD and Haplo donor remains uncertain and requires further exploration.

Alternative Donor Transplantation for Severe Aplastic Anemia: A Comparative Study of the Saawp EBMT

Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT INTRODUCTION Allogeneic stem cell transplantation (allo-SCT) from an HLA-matched sibling donor (MSD) is considered the standard of care for younger patients with severe aplastic anemia (SAA). For patients lacking a suitable MSD, matched unrelated donors (MUD) have increasingly been used for SAA patients who do not respond to immunosuppressive therapy. However, a significant number of SAA patients who require allo-SCT are unable to access a fully HLA-matched unrelated donor or experience delays in finding one. In such cases, other alternative options, such as mismatched unrelated donors (MMUD), and haploidentical family donors (Haplo), have been explored. Limited research exists on MUD, MMUD, and Haplo allo-SCT efficacy and safety in SAA. Drawing definitive conclusions for the optimal alternative donor transplant approach remains challenging. This study compares the outcomes of allo-SCT from MUD, MMUD, and Haplo donors in patients with SAA from the SAAWP EBMT. PATIENTS AND METHODS Inclusion criteria All patients diagnosed with SAA who underwent their first allo-SCT between January 2012 and December 2021 from either a MUD, MMUD or Haplo, were included. Only transplants from Haplo donors who received post-transplant cyclophosphamide (PTCy) as prophylaxis for graft-versus-host disease (GVHD) were considered. Statistical Analysis The study utilized statistical methods such as Kaplan-Meier estimation, Log-Rank test, competing risks analysis, and Cox proportional hazards regression. The analyses included OS, EFS, GRFS, NRM, aGVHD, cGVHD, and graft failure. The statistical software R and relevant packages were used. RESULTS Patient and Transplantation Characteristics Table 1 summarizes patient and transplant characteristics for the 1652 participants. Engraftment Neutrophil recovery at 28 days was 85% (95% CI; 83-87) for MUD, 84% (95% CI; 80-88) for MMUD, and 75% (95% CI; 69-81) for Haplo (p = 0.033). Platelet engraftment at 100 days was 88% (95% CI; 86-91) for MUD, 82% (95% CI; 78-87) for MMUD and 72% (95% CI; 65-78) for Haplo (p &amp;lt; 0.001). Graft failure The 1-year cumulative incidence of primary graft failure (PGF) for the MUD, MMUD, and Haplo cohorts was 4% (95% CI; 3-6%), 5% (95% CI; 3-8%) and 16% (95% CI; 11-21%), respectively (p &amp;lt; 0.001). In multivariable analysis, compared with MUD, Haplo (HR, 3.72; 95% CI, 1.97-7.03; p&amp;lt;0.001) was associated with a higher PGF. Other predictors for a higher PGF are shown in Table 2. GVHD The cumulative incidence of aGVHD grades II-IV at 100 days for the MUD, MMUD, and Haplo cohorts was 13% (95% CI; 11-15), 22% (95% CI; 17-26), and 18% (95% CI; 13-24), respectively (p &amp;lt; 0.001). In multivariable analysis, MMUD was associated with an increased risk of aGVHD grades II-IV, when compared with MUD (HR 1.97; 95% CI, 1.4-2.77; p &amp;lt; 0.001). Other predictors associated with a higher risk of aGVHD grades II-IV are shown in Table 2. The 3-year cumulative incidence of cGVHD for the MUD, MMUD, and Haplo cohorts was 18% (95% CI; 15-20), 19% (95% CI; 14-24), and 18% (95% CI; 11-24), respectively (p = 0.9). NRM The 3-year cumulative incidence of NRM was 12% (95% CI; 10-14) for MUD, 17% (95% CI; 13-22) for MMUD, and 22% (95% CI; 15-28) for Haplo (p &amp;lt; 0.001). Survival The 3-year EFS for the MUD, MMUD, and Haplo cohorts was 73% (95% CI; 71-76), 64% (95% CI; 59-70), and 53% (95% CI; 46-61), respectively (p &amp;lt; 0.001), whereas OS was 81% (95% CI; 79-84), 74% (95% CI; 69-79), and 63% (95% CI; 54-71), respectively (p &amp;lt; 0.001). In multivariable analysis, compared to MUD, MMUD (HR, 1.54; 95% CI, 1.12-2.11; p = 0.007) and Haplo (HR, 1.97; 95% CI, 1.35-2.86; p&amp;lt;0.001) were associated with worse survival. Other predictors for a worse OS are shown in Table 2. The 3-year GRFS for the MUD, MMUD, and Haplo cohorts was 71% (95% CI; 68-74), 66% (95% CI; 60-72), and 53% (95% CI; 44-61), respectively (p &amp;lt; 0.001). In multivariable analysis, compared with MUD, MMUD (HR, 1.42; 95% CI, 1.1-1.82; p = 0.006) and Haplo (HR, 1.71; 95% CI, 1.27-2.31; p&amp;lt;0.001) were associated with worse GRFS. Other factors associated with a worse GRFS are shown in Table 2. CONCLUSION In conclusion, our study supports MUD transplantation as the preferred option for SAA patients without a MSD. While MMUD and Haplo transplants are feasible, MMUD appears more favorable than Haplo, even in the era of PTCy.

The Characteristics of T Lymphocyte Reconstitution after Haploid Hematopoietic Stem Cell Transplantation in SAA and Its Relationship with aGVHD

To investigate the recovery characteristics of T cell subsets in patients with severe aplastic anemia (SAA) who received haploid hematopoietic stem cell transplantation(HSCT) and its relationship with acute graft-versus-host disease(aGVHD). The clinical data of 29 SAA patients who received haploid hematopoietic stem cell transplantation in the department of hematology, Shanxi Bethune Hospital from June 2018 to January 2022 were retrospectively analyzed. The absolute counts of CD3+T, CD4+T, CD8+T lymphocytes and the ratio of CD4+T/CD8+T lymphocytes in all patients before transplantation, 14, 21, 30, 60, 90 and 120 days after transplantation were analyzed. The proportion of T lymphocytes was compared in the non-aGVHD group, the grade Ⅰ-Ⅱ aGVHD group and the grade III-IV aGVHD group. The counts of all T cells in 27 patients were far below the normal level at 14 and 21 days after transplantation, but there was obvious heterogeneity. There was a certain relationship between T cell immune reconstitution and conditioning regimen, age, and immunosuppressive treatment before transplantation. CD3+T cells showed a steady upward trend at 30, 60, 90, and 120 days after transplantation, and returned to the normal levels at 120 days after transplantation; faster recovery of CD4+T cells was closely related to aGVHD, which was at 30, 60, 90, 120 days after transplantation showed a slow upward trend, and which was still far below the normal level of 120 days after transplantation. CD8+T cell counts began to recover at 14 and 21 days after transplantation, and the recovery was earlier than the CD4+T cells, and its recovery speed was rapid 30 and 60 days after transptantation, which showed an upward trend and exceeded the normal levels 90 days after transplantation. Since CD8+ T cells reconstituted quickly, while the CD4+ T cells reconstitution was slowly, which made the long-term CD4+T/CD8+T cell ratio after transplantation was inverted . Compared with the non-aGVHD group, the absolute counts of CD3+T, CD4+T, and CD8+T cells in the aGVHD group were significantly higher than those in the non-aGVHD group at each time period after transplantation. In the aGVHD group, grade Ⅲ-Ⅳ aGVHD occurred more frequently in the early post-transplantation period (within 14-21 days), the grade Ⅰ-Ⅱ aGVHD group mostly occurred within 30-90 days after transplantation, and CD3+T, CD4+T, CD8+T cell counts in the grade Ⅲ-Ⅳ aGVHD group were significantly higher than those in the grade Ⅰ-Ⅱ aGVHD group; and the greater the proportion of CD4+T, the more severe the degree of aGVHD. The speed of T cell immune reconstitution after SAA haploid transplantation is different, which is related to the conditioning regimen, age, and immunosuppressive therapy before transplantation. The rapid recovery of CD4+ T cells is closely related to the occurrence of aGVHD.

561 - Incidence and Outcome of Secondary Graft Failure in Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia: A Single Center Study

561 - Incidence and Outcome of Secondary Graft Failure in Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia: A Single Center Study

Haploidentical hematopoietic stem cell transplantation in severe aplastic anemia: time for long term and quality of life assessed studies

Haploidentical hematopoietic stem cell transplantation in severe aplastic anemia: time for long term and quality of life assessed studies

S239: COMPARABLE LONG-TERM OUTCOMES BETWEEN UPFRONT HAPLOIDENTICAL AND IDENTICAL SIBLING DONOR HSCT IN APLASTIC ANEMIA: A NATIONAL REGISTRY-BASED STUDY

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative option for severe aplastic anemia (SAA), and transplantation from identical sibling donors (ISDs) has been recommended as a first-line treatment. Aims: Haploidentical donor (HID) transplantation for SAA has made great advances; thus, an increased role of HID-SCT in SAA should be considered if an ISD is unavailable. Methods: We performed a national registry-based analysis comparing long-term outcomes in the upfront HID or upfront ISD SCT setting. Results: A total of 342 SAA patients were enrolled, with 183 patients receiving HID SCT and 159 receiving ISD SCT. The estimated 9-year overall survival (OS) and failure-free survival (FFS) were 87.1±2.5% and 89.3±3.7% (P = 0.173) and 86.5±2.6% vs. 88.1±3.8% (P = 0.257) for patients in the HID and ISD SCT groups, respectively. Transplantation from HID or ISD SCT has greatly improved quality of life (QoL) levels post-HSCT compared to pre-HSCT. The occurrence of chronic graft versus host disease was the only identified adverse factor affecting each subscale of QoL. Physical and mental component summaries in adults as well as physical, mental, social, and role well-being in children were all similar between HID and ISD SCT at 5-year points. At the last follow-up, the proportion of returning to society was comparable between the HID and ISD groups, showing 78.0% versus 84.6% among children and 74.6% versus 81.2% among adults. A total of 342 SAA patients were enrolled, with 183 patients receiving HID SCT and 159 receiving ISD SCT. The estimated 9-year overall survival (OS) and failure-free survival (FFS) were 87.1±2.5% and 89.3±3.7% (P = 0.173) and 86.5±2.6% vs. 88.1±3.8% (P = 0.257) for patients in the HID and ISD SCT groups, respectively. Transplantation from HID or ISD SCT has greatly improved quality of life (QoL) levels post-HSCT compared to pre-HSCT. The occurrence of chronic graft versus host disease was the only identified adverse factor affecting each subscale of QoL. Physical and mental component summaries in adults as well as physical, mental, social, and role well-being in children were all similar between HID and ISD SCT at 5-year points. At the last follow-up, the proportion of returning to society was comparable between the HID and ISD groups, showing 78.0% versus 84.6% among children and 74.6% versus 81.2% among adults. Image:Summary/Conclusion: These data suggest the recommendation for upfront transplantation with a haploidentical donor for SAA patients in the absence of an ISD, especially in experienced transplant centers.

Comparable long-term outcomes between upfront haploidentical and identical sibling donor transplant in aplastic anemia: a national registry-based study.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative option for severe aplastic anemia (SAA), and transplantation from identical sibling donors (ISD) has been recommended as a first-line treatment. Haploidentical donor (HID) transplantation for SAA has made great advances; thus, an increased role of HID-SCT in SAA should be considered. We performed a national registry-based analysis comparing long-term outcomes in the upfront HID or upfront ISD SCT setting. A total of 342 SAA patients were enrolled, with 183 patients receiving HID SCT and 159 receiving ISD SCT. The estimated 9-year overall survival and failure-free survival were 87.1±2.5% and 89.3±3.7% (P=0.173) and 86.5±2.6% versus 88.1±3.8% (P=0.257) for patients in the HID and ISD SCT groups, respectively. Transplantation from HID or ISD SCT has greatly improved quality of life (QoL) levels post-HSCT compared to pre-HSCT. The occurrence of chronic graft-versus-host disease was the only identified adverse factor affecting each subscale of QoL. Physical and mental component summaries in adults as well as physical, mental, social, and role well-being in children were all similar between HID and ISD SCT at 5-year time points. At the last follow-up, the proportion of returning to society was comparable between the HID and ISD groups, showing 78.0% versus 84.6% among children and 74.6% versus 81.2% among adults. These data suggest that haploidentical transplant can be considered a potential therapeutic option in the upfront setting for SAA patients in the absence of an HLA-identical related or unrelated donor.

Pre-Transplant Platelet Refractoriness and Alternative Donors Are Associated With Cytomegalovirus Retinitis in Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia.

BackgroundCytomegalovirus retinitis is a severe, vision-threatening opportunistic infection in an immunodeficient population. Reports on cytomegalovirus retinitis in hematopoietic stem cell transplant recipients due to severe aplastic anemia have been scant. This study assessed the risk of cytomegalovirus retinitis in relation to the pre-transplant status of severe aplastic anemia patients.MethodsWe conducted a retrospective nested case-control study of cytomegalovirus retinitis among severe aplastic anemia patients receiving allogeneic hematopoietic stem cell transplants in a tertiary care institution that attends severe aplastic anemia patients from southern China from January 1, 2013 to December 31, 2018. Each cytomegalovirus retinitis case was matched with four controls without cytomegalovirus retinitis by age and gender. Thirteen pre-transplant parameters were chosen to compare the risk factor levels between the cases and controls. Multivariable logistic regressions were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs).ResultsA total of 361 severe aplastic anemia patients received hematopoietic stem cell transplants in the study period 2013–2018 in our medical institution, and 31 (8.58%) developed cytomegalovirus retinitis. Cytomegalovirus retinitis was diagnosed in the median of 148 days after transplantation. We confirmed platelet refractoriness more frequently in cases than in controls (p = 0.0005). Compared with human leukocyte antigen-matched sibling donors, alternative donors were significantly more prone to cytomegalovirus retinitis (p = 0.0009). After stepwise selection in multivariate logistic regression, platelet refractoriness (OR 5.41, 95% CI 1.98–15.39), haploidentical donor (OR 7.46, 95% CI 2.19–34.87), and unrelated donor (OR 8.38, 95% CI 2.30–41.34) were associated with an increased risk of cytomegalovirus retinitis.ConclusionsPre-transplant platelet refractoriness and alternative donors were significant predictors of cytomegalovirus retinitis in severe aplastic anemia recipients. These results highlight the importance of accounting for existing risks while developing prevention strategies and preemptive treatment for severe aplastic anemia recipients. We recommend that the platelet count be closely monitored and thrombopoietin be properly applied during the period when cytomegalovirus retinitis is prone to occur.

Outcomes of a Novel Rituximab-Based Non-Ablative Conditioning Regimen for Hematopoietic Cell Transplantation in Severe Aplastic Anemia

IntroductionOlder patients with severe aplastic anemia (SAA) needing hematopoietic cell transplantation (HCT) typically require utilization of reduced intensity conditioning (RIC) regimens; however, use of RIC regimens in this population is limited by graft failure and transplant-related mortality due to toxicity and infections, particularly reactivation of Epstein-Barr virus (EBV). Novel RIC regimens with improved efficacy and decreased toxicity and risk of infectious complications are urgently needed to improve post-HCT outcomes for SAA patients.Patients and MethodsUtilizing institutional registries, we identified all SAA patients who underwent first allogeneic HCT using an FCR regimen (Figures 1A and 1B) between August 2014 and May 2017 at our institution for inclusion in this analysis. Post-transplant immune suppression comprised of tacrolimus and either methotrexate or mycophenolate mofetil. The Institutional Review Board approved this analysis and a waiver of informed consent was obtained. Medical records of all patients were reviewed by participating investigators. Assessment of graft-versus-host disease (GVHD) was performed following standard grading practice. An analysis of 1-year GVHD-free, relapse-free survival (GRFS) was conducted and compared to an historical cohort of all SAA patients transplanted with a non-FCR regimen at our institution since January 1999 (n=27), with differences between the curves determined using log-rank tests.Results11 SAA patients underwent HCT from August 1, 2014 to May 5, 2017, the majority of which were male with a median age of 41 years (range: 19-64). Most patients received one line of treatment prior to HCT (CSA+ATG=6, CSA=1, steroids=1) and received an HCT within a median of 205 days after diagnosis (range: 70-2090). All patients received transplants from matched or haploidentical donors (matched related=4, matched unrelated=5, haploidentical=2) using a peripheral blood stem cell source, except 1 patient who received a bone marrow graft. At median follow-up of 302 (range: 49-911) days post-transplant, all patients were alive and in remission with 100% donor peripheral blood chimerism with bone marrow biopsies documenting normal trilineage hematopoiesis. Average time to neutrophil and platelet engraftment was 15.4 days and 16 days, respectively. The median number of inpatient hospital days required in the first 100 days post-transplant was 11 days (range: 3-29). By day 100 post-transplant, 54.5% of patients developed some degree of acute GVHD (grade I=1, grade II=3, grade III=2). However, by date of last follow-up, all evaluable patients (10/11) had not developed chronic GVHD. Only 2 patients experienced a viral reactivation (1=cytomegalovirus (CMV), 1=CMV+EBV) by date of last follow-up post-transplant. The case of EBV reactivation did not require treatment and no patients developed post-transplant lymphoproliferative disorder. The unadjusted Kaplan-Meier estimate of 1-year GRFS was 81.8% (95% CI: 59.1-104.7%) in the study group versus 61.5% (95% CI: 42.9-80.1%) in the historical group (P=0.256) (Figure 1C) with death accounting for the greatest proportion of GRFS events in the historical population and grade III acute GVHD accounting for the two GRFS events in the study cohort.ConclusionsThe positive results from this study demonstrating low toxicity, GVHD, and EBV reactivation rates with no graft failure or relapse potentially justify the use of these novel outpatient non-myeloablative conditioning regimens in SAA patients of any age receiving transplantation from any donor source. Further prospective investigation in a larger population is warranted. [Display omitted] DisclosuresGatwood:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Byrne:Pfizer: Membership on an entity's Board of Directors or advisory committees; Concert Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding. Jagasia:Therakos: Consultancy, Research Funding; Mallinckrodt: Consultancy; Janssen: Consultancy, Research Funding. Savani:Jazz Pharmaceuticals: Speakers Bureau.

Post-Transplantation Cyclophosphamide and Short-Term Methotrexate for Tolerance Induction in HLA-Haploidentical Transplantation for Severe Aplastic Anemia

Background. Haploidentical related donors (HIDs) are attractive donors for patients with severe aplastic anemia (SAA) because they are readily available for nearly all the patients. Bone marrow transplant (BMT) using post-transplant cyclophosphamide (PTCy) has been shown effective to cross the immune barriers between the recipients and their HIDs. Short-term low dose of methotrexate (ST-MTX) has long been adopted either alone or combined with calcineurin inhibitors to get across the immune barrier in hematopoietic stem cell transplant (HSCT).Aim of the study. We presented the outcome of 15 patients with SAA who underwent haploidentical transplant (HIT) using T-cell-replete peripheral graft and combination of PTCy with ST-MTX.Patients and grafts. We analyzed the medical records of 15 patients with SAA between Jan 2015 and July 2017. The transplants were either upfront (8/15) or rescue treatment (7/15). The median age of the patients was 16 (range 5-39) years and 66.7% (10/15) were male. All the patients received granulocyte colony-stimulating factor (G-CSF) mobilized peripheral graft from haploidentical related donors. The median mononuclear cells (MNCs) was 12.4 × 108 cells/kg recipient ideal body weight (IBW) with the range of (7.0-22.0) × 108 cells/kg, the CD34+ cell was 7.5 × 106 cells/kg with the range of (5-23) × 106 cells/kg and the CD3+ cells was 2.7 × 108 cells/kg with the range of (1.8-5.0) × 108 cells/kg.Conditioning regimen and GvHD prophylaxis. We used a TBI-free transplantation platform named FBC+PTCy/ST-MTX. Fludarabine was administered at 40 mg/m2 IV daily for 5 days. Busulfan was delivered in a total dose of 6.4mg/kg. Cyclophosphamide was given 14.5 mg/kg daily for 2 days. PTCy was administered at 60mg/kg/day IV on days +3 and +4 post-transplant. Low doses of MTX were delivered on days +1, +2 and +5 post-transplant at 15mg/m2, 10mg/m2 and 10mg/m2. Cyclosporine was given from day +6 through day +180 with the target through level 150~180ng/ml and then was tapered until 12 months post transplant. Mycophenolate mofetil (MMF) was given from day +6 to +35 days for the first 3 patients and then was eliminated for the following patients.Results.Neither primary nor secondary graft failure (GF) was seen in this study. Neutrophil engrafted at 15 days (range, 13-18 days). Platelets engrafted at 19 days (range, 14-36 days) and recovered over 100 × 109/L at 38 days (range, 14-77 days). The time to total lymphocytes recovery over 0.5 × 109/L for 3 consecutive days was 34 days (range, 25-72 days). The accumulated engraftment of neutrophil and platelets were both 100% at +40 days. (Figure 1-A, B.)The cumulative incidence of aGvHD at 100 days was 20.0%(3/15). Two patients had grade I skin aGvHD and the other one had grade II skin aGvHD. No grade III-IV aGvHD was seen. 12 patients were evaluable for the incidence of cGvHD and none of them developed moderate or sever cGvHD with a median of 150 (102-806) days post transplant. (Figure 1-C, D.) During the follow-up, one patients had skin cGvHD and received systemic therapy with corticoid. The treatment was discontinued after 8 months post transplant. All 3 patients, who survived beyond 12 months post transplant at the end of our follow-up, were off immunosuppress.With a median follow-up of 230 days (range 41-806 days), all the patients are alive. They are transfusion independent with karnofsky performance status scale (KPS) scores 100.Conclusion.This study shows that haploidentical related transplant can be successfully applied using T-cell-repleted peripheral grafts. ST-MTX may facilitate PTCy to achieve a stable engraftment with a minimal risk of GvHD in HIT for patients with SAA. Our approach should expand the donor pool for patients with SAA. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Peripheral Stem Cell Transplantation Versus Bone Marrow Transplantation in Severe Aplastic Anemia - a Cohort of 149 Patients from a Single Medical Center in Taiwan

Background•The incidences of Aplastic anemia (AA) vary, reportedly being lower in North America and Europe, and three to five times higher in Asia.•Definitive therapy for AA include hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST).•In patients whose age > 40 and without HLA-MSD, IST with horse anti-thymocyte globulin (h-ATG) and cyclosporine are still the first choice but h-ATG is not available in some Asia, including Taiwan. Hence, allogeneic HSCT for Asian SAA patients might be of more importance.•The use of peripheral blood stem cell transplantation (PBSCT) has increased in recent years in the majority of centers, but bone marrow (BM) was the preferable graft source in recipients in previous studies, so there are insufficient data to support the use of PBSCT.•We conducted a cohort study to report the outcomes of SAA patients receiving allogeneic HSCT.Methods•SAA patients receiving allogeneic HSCT consecutively between 1985 and 2015 were enrolled. All patients were followed up until death, and the date of latest follow-up, or April 31, 2016. The maximum follow-up period was 31 years. Patients receiving cord blood stem cell transplant were excluded because of a large proportion of graft failures reported.•Rather than the standard conditioning regimen: Cyclophosphamide 200mg/kg (CY-200) and ATG, we used CY-200 and total body irradiation (TBI) (range 200-1,200 cGy). Rabbit ATG (r-ATG) was added additionally in the conditioning regimen for 59 (39.6%) patients at physicians' discretion.•We used chi-square tests or Fisher's exact test to compare the categorical variables between the two groups. Data are presented as medians and interquartile ranges (IQR) for skewed data. The cutoff value of time to HSCT (i.e., three months) and transplant year (year 2000) was chosen according to the median.•The primary endpoint was mortality. The survival probability was estimated using the Kaplan-Meier method. The risk factors for mortality were calculated using a Cox proportional hazards model, and hazard ratios (HRs) and the 95% confidence intervals (CIs) were calculated. We used a multivariate Cox proportional hazards model to identify risk factors for mortality while adjusting for possible independent confounding factors. All risk factors with p < 0.1 in the univariate model were entered into the multivariate analysis. All statistically significant levels were set at p < 0.05.Results•A total of 151 SAA patients were identified. Two patients receiving cord blood transplantation were excluded.•The median age at transplant was 24 (IQR 14-31 years), and 64 (43.0%) were male. The median time to HSCT was three months (IQR 1.9-6.9 months).•The Clinical characteristics of the cohort are shown in Table 1. The patients receiving HSCT from unrelated donors versus sibling donors, more receiving peripheral blood stem cell than bone marrow as graft source in unrelated donors•The overall survival rate (OS) was 76.0% within 31 years of follow-up (Figure 1).•Eight patients (5.4%) failed engraftment, including seven primary graft failures and one secondary graft failure after seven years of transplantation. Two of them received second allogeneic HSCT and survived. Incidences of acute and chronic GVHD were 24.8% and 33.6%, respectively.•The causes of mortality are shown in Figure 2. Infection was the leading cause of mortality•The analysis of the risk factors of mortality is detailed in Table 2.•Seven patients (4.7%) developed posttransplant malignancies, including four cases of posttransplant lymphoproliferative disease (PTLD), two cases of head and neck squamous cell carcinoma (SCC) and one case of esophageal SCC. Only one patient of PTLD died.Conclusion•In the lack of h-ATG, we adopted CY 200-TBI as the conditioning regimen rather than the standard CY 200-ATG and reported OS of 76.0% in 149 SAA patients receiving allogeneic HSCT in Taiwan. Infection is still the major mortality cause and should be monitored cautiously.•Despite TBI as a concern for developing malignancies, only one patient in our cohort died of PTLD.•We have identified the age at transplantation of ≥ 30, conditioning regimen with TBI > 300 cGy, and transplant year < 2000 were independent predictors of death, indicating the outcomes improved chronologically.•The comparison between PBSC and BMSC remained an unresolved issue so far. Herein, PBSCT is not a risk factor for death versus BMT in our cohort. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Analysis of CMV Infection after Allogeneic Hematopoietic Stem Cell Transplantation in Severe Aplastic Anemia

To investigate the clinical characteristics and risk factors of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with severe aplastic anemia (SAA). Clinical data from 270 SAA patients with allo-HSCT were retrospectively analyzed, including 108 sib congruence patients and 162 substitute donors (68 unrelated donor congruence patients and 94 related haploid patients). Different pretreatment schemes were selected for different transplantation modes. The HLA-identical sibling and haploid grafts were all bone marrow and peripheral blood stem cells, and the grafts from unrelated donors were peripheral blood stem cells. After granulocyte implantation, blood CMV-DNA was regularly monitored. Flow cytometry was also used to determine the absolute number of CD3+, CD4+T lymphocytes and CD19+B lymphocytes at 1, 2, 3, 6 and 12 months after transplantation. CMV infection occurred in 229 of 270 patients with an incidence of 84.8%. Among them, 18 patients developed giant cell disease. Univariate analysis showed that alternative donors (unrelated total and haploid donors), mycophenolate mofetil and acute graft-versus-host disease were statistically significantly associated with CMV infection (P<0.05). Multivariate analysis showed that alternative donors were associated with CMV infection. The recovery of CD3+ and CD4+ in 6 months in the substitute donors was delayed in comparison with that in the full sib group. After allo-HSCT, substitute donors are more easily to develop CMV infection than full-sibling donors, and the reconstruction of immune function is delayed after transplantation.

Optimizing outcomes for haploidentical hematopoietic stem cell transplantation in severe aplastic anemia with intensive GVHD prophylaxis: a review of current findings

ABSTRACT Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has resulted in increased levels of disease-free survival in severe aplastic anemia (SAA). Haploidentical transplantation (haplo-SCT) was previously not recommended due to unacceptable incidences of graft-versus-host disease (GvHD) and graft failures. With the advent of intensive GvHD prophylaxis strategies, the outcomes obtained with haplo-SCT for SAA have gradually improved. Areas covered: A comprehensive search considered PubMed reported articles before 1 February 2021, presented abstracts, and clinical trials pertaining to haplo-HSCT for SAA. This manuscript covers modern approaches with intensive GvHD prophylaxis in haplo-SCT for SAA. The representative methods consist of granulocyte colony stimulating factor (G-CSF) plus ATG-based and posttransplantation cyclophosphamide (PT-Cy)-based protocols. Expert opinion: Currently, haplo-SCT has become a feasible option for treating SAA. The G-CSF/ATG-based protocol included the largest sample size and reported comparable survival rates with identical siblings. The PT-Cy protocol resulted in a relatively lower incidence of GvHD and seemingly poorer but continuously improved engraftment with augmented conditioning. The optimized outcomes are constantly updated with the modification of the conditioning regimen, donor selection, graft source and GvHD prophylaxis. In the future, we should pay more attention to quality of life in addition to survival, and personalized haplo-SCT may improve outcomes.

The incidence, clinical outcome, and protective factors of mixed chimerism following hematopoietic stem cell transplantation for severe aplastic anemia.

The aim of our study was to determine possible predictors and clinical course of mixed chimerism (MC) in aplastic anemia after transplantation. A total of 207 transplants were obtained from haploidentical donors (HID) using busulfan (Bu), cyclophosphamide (Cy), and anti-thymocyte globulin (ATG) regimens, and 69 transplants from matched related donors (MRD) and 29 transplants from unrelated donors (URD) using Cy/ATG regimens were obtained. Incidences of MC were 1.93±0.01%, 20.29±0.01%, and 35.71±0.01% in HID, MRD, and URD transplantation (p<.001). In multivariate analysis, incidence of MC was significantly higher in patients without adding Bu in conditioning (p<.001) and receiving a lower number of CD3+cells in graft (p=.042). MC was associated with significantly lower II-IV aGvHD (3.70% vs. 27.7%, p=.007), but higher secondary graft rejection rates (14.8% vs. 0.4%, p<.001) and poorer overall survival (72.7±8.9% vs. 89.6±2.0%, p=.011) than those of donor chimerism cohort. Mixed chimerism was an unsettling status even in non-malignancy. Haploidentical transplantation with more intense regimen by adding Bu to Cy and ATG was associated with reduced MC following HSCT for SAA. An intensified regimen should be explored in matched related or unrelated donors.

Long-term results of allogeneic peripheral blood hematopoietic stem cell transplantation for severe aplastic anemia

ObjectiveAplastic anemia (AA) is a life-threatening disorder and may be associated with significant morbidity and mortality Currently, the first treatment option is allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients younger than 40 years. Bone marrow is recommended as the stem cell source due to less graft versus host disease (GVHD) risk and better outcomes than peripheral blood (PB)-derived stem cell. The aim of this study is to share the data of AA patients who have underwent PB-derived allo-HSCT in our bone marrow transplantation center. MethodsTwenty-seven patients who underwent PB-derived allo-HSCT from human leukocyte antigen matched sibling donors were analyzed retrospectively. ResultsThe median follow-up time was 95.2 months (range, 4.8–235 months). The 10-year survival was 89 %. The median neutrophil and platelet engraftment time was 11 days (range, 9–16 days) and 13 days (range, 11–29 days), respectively. Primary platelet engraftment failure was observed in 1 patient (3.7 %). Acute and chronic GVHD observed in 2 (7.4 %) and 3 (11.1 %) patients, respectively. Neutropenic fever was observed in 13 (44.8 %) of patients until the engraftment after allo-HSCT. One patient died due to CMV infections, two died due to septic shock secondary to fungal infection. ConclusionAlthough there is no prospective data directly comparing BM with PB as stem cell source in AA, observational studies indicates better OS with BM. PB can be used in certain situations such as higher risk for graft failure and donor preference. This study demonstrated that PB-derived stem cell seems to be a reasonable alternative to BM.

Mixed chimerism after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia

ABSTRACT Background: Mixed chimerism (MC) frequently occurs in patients with severe aplastic anemia (SAA) after allogeneic hematological stem cell transplantation (allo-HSCT). Methods A retrospective study on 287 patients with SAA who underwent allo-HSCT between October 2012 and January 2020 was conducted to explore the outcomes, risk factors and treatment options for MC. Among 287 AA patients who excluded Fanconi anemia (FA), Congenital dyskeratosis (DKC), Paroxysmal nocturnal hemoglobinuria (PNH), etc.112 underwent matched sibling donor (MSD)-HSCT, 91 matched unrelated donor-HSCT and 84 haploidentical-HSCT. Patients were divided into the following 4 groups: group 1: Donor chimerism (DC); group 2: MC without cytopenia; group 3: MC with cytopenia; group 4: secondary graft failure (SGF). Results Compared with the other three groups, SGF predicted a poor prognosis of SAA (P< 0.001). In addition, SGF was associated with the early (within 3 months after transplantation) presence of MC and the high levels of MC. Uni- and multivariate logistic regression analysis showed that donor/recipient sex-mismatching and CTX + ATG regimen were high-risk factors for MC. Of note, in MC patients with cytopenia (group 3), the effective response rate reached 55% (6/11) following enhanced immunosuppression combined with cellular therapy, while only one of the four was effective who received enhanced immunosuppression alone. Conclusion SGF was associated with poor prognosis, early presence of MC and increased levels of recipient chimerism. The donor/recipient sex-mismatching and CTX + ATG regimen based MSD-HSCT were risk factors for MC. Cellular therapy could improve the effective response rate of patients with progressive MC.

Haploidentical stem cell transplantation for aplastic anemia: the current advances and future challenges.

Haematopoietic stem cell transplantation (HSCT) is a curative option for severe aplastic anemia (SAA). Finding a suitable matched donor in a timely manner is a challenge. The availability of haploidentical donors and their successful use in transplantation have expanded valid choices for SAA. In recent decades, haploidentical HSCT (haplo-HSCT) for the treatment of SAA has been continuously attempted, and great strides have been made. Nowadays, haplo-HSCT using different regimens has overcome the difficulty of graft failure and severe graft-versus-host disease (GvHD), and achieved inspiring survival outcomes in SAA. The regimens consist mainly of granulocyte colony-stimulating factor (G-CSF) plus antithymocyte globulin (ATG), posttransplantation cyclophosphamide (PT-Cy), and ex vivo graft T-cell depletion (TCD). In particular, the G-CSF and ATG-based regimen includes the largest sample size and the successful wide use of the G-CSF and ATG-based regimen has promoted haplo-HSCT a higher priority in SAA patients without matched related or unrelated donors in China. Recent studies have also indicated that haplo-HSCT using PT-Cy or TCD regimen is a practicable alternative, but the sample size is relatively small. Here, we offer an overview of clinical results obtained through the use of haploidentical transplantation in SAA, mainly focusing on current advances and future challenges.

Bone Marrow Transplantation for Severe Aplastic Anemia: Has Outcome Improved?

AbstractBone marrow transplants for severe aplastic anemia were first performed in the 1970s. Transplant regimens, supportive care, and patient selection have changed substantially since then. Our objective was to determine the impact of these changes on transplant outcome. We studied 1,305 recipients of HLA-identical sibling transplants for aplastic anemia between 1976 and 1992, reported to the IBMTR by 179 centers. We compared survival of transplants performed in three intervals (1976 through 1980 [n = 186], 1981 through 1987 [n = 648], and 1988 through 1992 [n = 471]) using Cox proportional hazards regression. Five-year survival (±95% confidence interval) increased from 48% ± 7% in the 1976-1980 cohort to 66% ± 6% in the 1988-1992 cohort (P < .0001). Risks of graft-versus-host disease (GVHD) and interstitial pneumonia decreased over time, but the risk of graft failure did not. Higher long-term survival resulted primarily from decreased mortality in the first 3 months posttransplantation. Late mortality risks were low and changed little over the intervals studied. In multivariate analysis, changes in transplantation strategies accounted for most but not all of the improved outcome. Use of cyclosporine to prevent GVHD was the most important factor. Changes in patient selection did not seem to explain improved survival. Survival after HLA-identical sibling bone marrow transplantations for aplastic anemia has improved since 1976. Changes in GVHD prophylaxis account for much of this improvement. Other changes may also operate.

Long-term results of allogeneic peripheral blood hematopoietic stem cell transplantation for severe aplastic anemia

Abstract Objective Aplastic anemia (AA) is a life-threatening disorder and may be associated with significant morbidity and mortality Currently, the first treatment option is allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients younger than 40 years. Bone marrow is recommended as the stem cell source due to less graft versus host disease (GVHD) risk and better outcomes than peripheral blood (PB)-derived stem cell. The aim of this study is to share the data of AA patients who have underwent PB-derived allo-HSCT in our bone marrow transplantation center. Methods Twenty-seven patients who underwent PB-derived allo-HSCT from human leukocyte antigen matched sibling donors were analyzed retrospectively. Results The median follow-up time was 95.2 months (range, 4.8–235 months). The 10-year survival was 89 %. The median neutrophil and platelet engraftment time was 11 days (range, 9–16 days) and 13 days (range, 11–29 days), respectively. Primary platelet engraftment failure was observed in 1 patient (3.7 %). Acute and chronic GVHD observed in 2 (7.4 %) and 3 (11.1 %) patients, respectively. Neutropenic fever was observed in 13 (44.8 %) of patients until the engraftment after allo-HSCT. One patient died due to CMV infections, two died due to septic shock secondary to fungal infection. Conclusion Although there is no prospective data directly comparing BM with PB as stem cell source in AA, observational studies indicates better OS with BM. PB can be used in certain situations such as higher risk for graft failure and donor preference. This study demonstrated that PB-derived stem cell seems to be a reasonable alternative to BM.

Hematopoietic Cell Transplantation with Cryopreserved Grafts for Severe Aplastic Anemia.

With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P = .01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P = .0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.