HLA-matched Sibling Transplantation Research Articles

Bone Marrow Versus Peripheral Blood in HLA-Matched Sibling Transplantation: Does the Stem Cell Source Matter in Severe Aplastic Anemia?

Background Selecting a graft source is critical in HLA-matched sibling donor hematopoietic stem cell transplantation (MSD-HCT) for severe aplastic anemia (SAA). Since graft-versus-host-disease (GVHD) is the major cause of mortality after MSD-HCT, and SAA patients do not need the graft-versus-leukemia effect, the selection of a suitable source of stem cells becomes critical. Although bone marrow (BM) is the preferable stem cell source based on the registry-based studies, mobilized peripheral blood stem cells (PBSC) may offer faster engraftment with rapid immune reconstitution. Moreover, the recent advances in conditioning regimens have significantly reduced transplantation-related complications. Here, we compared the long-term outcomes of BM vs PBSC as a graft source in adult patients with SAA who received MSD-HCT with the reduced intensity conditioning (RIC) regimen. Method We conducted a retrospective analysis of 171 consecutive SAA adult patients who received MSD-HCT with Flu6/Cy2/ATG4 RIC regimen (Flu, 30 mg/m 2 IV for 6 days: Cy, 50 mg/kg IV for 2 days; rabbit ATG, 2.5 mg/kg IV for 4 days) or total nodal irradiation (TNI) of 750 cGy combined with ATG as GVHD prophylaxis (TNI-750/ATG) from March 2002 to March 2021 at Seoul St. Mary's Hospital, Seoul, Korea. BM was the primary graft source, but PBSC was used in donors who refused BM harvest, were unsuitable for general anesthesia, or received TNI-750/ATG conditioning. The primary endpoint of this study was to compare the overall survival (OS), and the secondary endpoints included speed of hematologic recovery, primary or secondary graft failure (GF), and failure-free survival (FFS) between the BM and PBSC group. Results The median patient age in the BM group was 38 years (range, 15 - 59) and 44 years (range, 19 - 64) in the PBSC group (p=0.005). There were no differences of baseline characteristics between the two groups except for a donor-to-recipient sex discrepancy (female to male, BM vs. PBSC; 16.4% vs. 30.9%, p=0.029). The majority of BM group (114/116, 98.2%) received the Flu6/Cy2/ATG4 RIC regimen, while 38.2% (21/55) of PBSC group received TNI-750/ATG for the conditioning (p<0.001). The PBSC contained a median 4.71 (range, 1.22 - 17.03) x 10 6/kg CD34 + cells and 368.82 (range, 25.12 - 1234.70) x 10 6/kg CD3 + cells which were about 1.7-fold (BM 2.80 x 10 6/kg CD34 + cells; range, 0.25 - 10.05) and 10-fold (BM 39.61 x 10 6/kg CD3 + cells; range, 1.34 - 463.68) higher than the BM graft (p<0.001). Consequently, the PBSC group exhibited faster engraftment of neutrophils (median 13 vs. 11 days, p<0.001) and platelets (median 18 vs. 12 days, p=0.012). However, there were no differences in the incidence of secondary GF (19.0% vs. 12.7%, p=0.386) and donor-type aplasia (4.3% vs. 10.9%, p=0.178) between two groups. Furthermore, the incidence of acute grade I-II (8.6% vs. 10.9%, p=0.619) and moderate to severe chronic graft-versus-host disease (GVHD) (3.5% vs. 5.5%, p=0.542) were also not significantly different between two groups. However, the BM group has shown more CMV reactivation (44.0% vs. 24.9%, p=0.005), and higher incidence of respiratory infection (14.7% vs. 3.6%, p=0.037) than those of the PBSC group. The incidences of transplantation-related complications between the BM and PBSC group are summarized in Table. The 10-year OS (93.8% vs. 98.1%, p=0.246) and FFS (65.7% vs. 69.0%, p=0.455) were comparable (Figure). Moreover, there was no significant difference in FFS between BM and PBSC group by potential risk factors of patient and donor age at MSD-HCT, sex incompatibility, ABC mismatch, PNH clone presence, HCT-CI ≥3, infused CD34 + cell count, interval from diagnosis to transplant, prior IST history, heavy transfusion before allo-HCT, or severity of AA. Conclusions Our results suggest that survival outcomes of MSD-HCT showed no difference between BM and PBSC as graft sources, and using PBSC may be an efficient alternative offering faster engraftment without significant difference in graft failure or transplantation-related adverse events such as GVHD, and survival. Current analysis and results were drawn from the Asian population with a fludarabine-based conditioning regimen and therefore, need to validate in the Western population. In addition, well-designed prospective studies in a larger cohort are required to confirm our findings.

Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n=331) or single-unit unrelated cord blood (UCB) (n=668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P=0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P=0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P=0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P=0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P<0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P<0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P<0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P<0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

Haploidentical Stem Cell Transplantation Had a Lower Incidence of Bronchiolitis Obliterans Syndrome Compared with HLA-Matched Sibling Transplantation for Patients with Hematologic Malignancies: Benefit from ATG?

Background: Haploidenticalstem cell transplantation(HID-SCT) based on antithymocyte globulin (ATG) GVHD prophylaxis had achieved similar incidence of cGVHD with HLA-matched sibling transplantation (MSD-SCT). However, bronchiolitis obliterans syndrome (BOS) serve as pulmonary cGVDH, was rarely compared between HID and MSD transplantation. Methods: One thousand four hundred and five patients with hematologic malignancies underwent SCT were enrolled in this retrospective study. Based on donor type, we divided the patients into three groups: HID, MSD and MUD (match unrelated donor) groups. All patients in HID and MUD group received ATG for GVHD prophylaxis, and the minority of patients in MSD group because of clinical trials. The vast majority of HID-SCT recipients transplanted with mixed grafts (bone marrow plus peripheral blood stem cell), whereas most MSD-SCT and all MUD-SCT recipients received PBSC (peripheral blood stem cell) grafts. The cumulative incidences and risk factors of BOS were analyzed. Results: The 5-year cumulative incidence of BOS was 7.2% in the whole population. HID transplantation had lower 5-year cumulative incidence of BOS than MSD transplantation (4.1% vs 10.0%; p<0.001), and the similar incidence with MUD transplantation (4.1% vs 6.2%; p=0.224). The 5-year cumulative incidence of BOS was lower in ATG group than that in non-ATG group in the whole and MSD population both (4.6% vs 11.2%; p<0.001; and 4.1% vs 11.2%; p=0.042, respectively). The 5-year incidence of BOS in mixed grafts group was also lower than that in PBSC group (4.2% vs 9.1; p=0.001). Multivariate analysis showed that HID, ATG and mixed grafts were protective factors for BOS (OR 0.3; 95%CI, 0.2 to 0.6; p<0.001; OR 0.3; 95%CI, 0.2 to 0.7; p=0.001; OR 0.3; 95%CI, 0.1 to 0.8; p=0.013), and aGVHD and cGVHD were independent risk factors for BOS (OR 2.1; 95%, 1.1 to 4.3; p= 0.035; OR 10.1; 95%CI, 4.0 to 25.0; p<0.001). Conclusions: HID transplantation had a lower incidence of BOS than MSD transplantation, which might be associated with ATG and mixed grafts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Unrelated cord blood transplantation vs. HLA-matched sibling transplantation for adults with B-cell acute lymphoblastic leukemia in complete remission: superior OS for patients with long-term survival

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important curative therapy for adult acute lymphoblastic leukemia (ALL). For patients who lack a human leukocyte antigen (HLA)-matched sibling donor, unrelated cord blood (UCB) is an alternative graft option. Previous studies have focused mainly on all T- and B-cell ALL (B-ALL) patients, while data related specifically to adult B-ALL patients after UCB transplantation (UCBT) are scarce.MethodsWe retrospectively compared the outcomes of UCBT and HLA-matched sibling transplantation (MST) in the treatment of adult B-ALL patients in complete remission (CR) at our center. From June 2006 to December 2020, 156 adult B-ALL patients who achieved CR before transplantation were enrolled. The main clinical outcomes of UCBT and MST were analyzed.ResultsHematopoietic recovery was significantly faster in MST recipients than in UCBT recipients. Higher incidences of grades II-IV and III-IV acute graft-versus host disease (aGVHD) were found in UCBT recipients (P < 0.001 and = 0.03), while a lower incidence of extensive chronic GVHD (cGVHD) was found in UCBT recipients (P < 0.001). The cumulative incidences of 2-year non-relapse mortality (NRM), 2-year relapse, 5-year disease-free survival (DFS) and 5-year GVHD-free relapse-free survival (GRFS) were comparable between MST and UCBT recipients. The overall survival (OS) during the first 700 days was similar between the MST and UCBT groups, while the OS of patients with a survival time of more than 700 days in the UCBT group was better than that in the MST group according to multivariate analysis (P = 0.03).ConclusionsOur study shows that when treating adult B-ALL patients in CR, UCBT can achieve comparable effects as MST, may provide superior OS for patients with long-term survival, and should be considered a good alternative.

Post-Transplantation Cyclophosphamide Versus Tacrolimus and Methotrexate Graft-Versus-Host Disease Prophylaxis for HLA-Matched Donor Transplantation

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is increasing in patients undergoing HLA-matched sibling (MSD) or unrelated (MUD) donor hematopoietic cell transplantation (HCT), but data about its comparative efficacy against the traditional GVHD prophylaxis are scarce. Two broad questions assessed in this study were (a) comparison of PTCy-based GVHD prophylaxis versus Tac/MTX (without ATG) in the MSD and (b) comparison of PTCy-based GVHD prophylaxis versus Tac/MTX (with ATG) in the MUD group. This retrospective single-center study analyzed the outcomes of 964 patients who received Tac/MTX (n=578) versus PTCy-based (n=386) GVHD prophylaxis. All MUD recipients in the Tac/MTX group also received ATG; thus separate analyses were conducted for MSD (n=412) and MUD (n=552) cohorts. In the MUD cohort, 306 patients received Tac/MTX/ATG and 246 received PTCy-based GVHD prophylaxis. In the MSD cohort, 272 received Tac/MTX and 140 received PTCy-based prophylaxis. Both PTCy groups included somewhat older patients than the Tac/MTX groups and more patients had myeloid malignancy (85%-90% versus 59%-64%, respectively). A majority of patients in all groups received myeloablative conditioning and peripheral blood graft. Both PTCy groups had a significantly delayed neutrophil engraftment, higher risk of hemorrhagic cystitis, and higher risk of bacterial infections than the Tac/MTX groups. The risks of viral infections and related deaths were significantly higher in Tac/MTX group in the MUD cohort. In multivariate analysis, the risk of grade III-IV acute GVHD was similar in PTCy and Tac/MTX groups in both MSD and MUD cohorts, but the risk of chronic GVHD was significantly lower with PTCy in the MSD cohort. PTCy was associated with a significantly lower risk of non-relapse mortality and better progression-free survival in the MUD. PTCy was associated with improved GVHD-free relapse-free survival in both MSD and MUD groups. Our data suggest a benefit of using PTCy-based GVHD prophylaxis in both MSD (versus Tac/MTX) and MUD (versus Tac/MTX/ATG) HCT.

CMV infection combined with acute GVHD associated with poor CD8+ T-cell immune reconstitution and poor prognosis post-HLA-matched allo-HSCT.

Cytomegalovirus (CMV) infection and acute graft-versus-host disease (aGVHD) are two major complications that contribute to a poor prognosis after hematopoietic stem cell transplantation (HSCT). Superior early immune reconstitution (IR) is associated with improved survival after HSCT. However, when all three factors, CMV infection, aGVHD, and IR, are concomitantly considered, the effects of the triple events on HSCT are still unknown and should be studied further. Thus we enrolled 185 patients who were diagnosed as hematological malignancies and treated with HLA-matched sibling transplantation (MST) between January 2010 and December 2014, of whom 83 were positive for CMV infection and 82 had aGVHD. Results showed that patients with both aGVHD and CMV infection had significantly higher non-relapse mortality (NRM), lower overall survival (OS), and delayed CD8+ T-cell IR. Multivariate analyses showed that both aGVHD combined with CMV infection and delayed CD8+ T-cell IR were independent risk factors for prognosis post-MST. Recurrent CMV infections are associated with poor CD8+ T-cell reconstitution. However, superior IR could protect against the negative effects of aGVHD and CMV infection on the transplant outcomes.

Haploidentical transplantation has a superior graft-versus-leukemia effect than HLA-matched sibling transplantation for Ph- high-risk B-cell acute lymphoblastic leukemia.

Background:Compared with human leukocyte antigen (HLA)-matched sibling donor (MSD) transplantation, it remains unclear whether haploidentical donor (HID) transplantation has a superior graft-versus-leukemia (GVL) effect for Philadelphia-negative (Ph–) high-risk B-cell acute lymphoblastic leukemia (B-ALL). This study aimed to compare the GVL effect between HID and MSD transplantation for Ph– high-risk B-ALL.Methods:This study population came from two prospective multicenter trials (NCT01883180, NCT02673008). Immunosuppressant withdrawal and prophylactic or pre-emptive donor lymphocyte infusion (DLI) were administered in patients without active graft-versus-host disease (GVHD) to prevent relapse. All patients with measurable residual disease (MRD) positivity posttransplantation (post-MRD+) or non-remission (NR) pre-transplantation received prophylactic/pre-emptive interventions. The primary endpoint was the incidence of post-MRD+.Results:A total of 335 patients with Ph– high-risk B-ALL were enrolled, including 145 and 190, respectively, in the HID and MSD groups. The 3-year cumulative incidence of post-MRD+ was 27.2% (95% confidence interval [CI]: 20.2%–34.7%) and 42.6% (35.5%–49.6%) in the HID and MSD groups (P = 0.003), respectively. A total of 156 patients received DLI, including 60 (41.4%) and 96 (50.5%), respectively, in the HID and MSD groups (P = 0.096). The 3-year cumulative incidence of relapse was 18.6% (95% CI: 12.7%–25.4%) and 25.9% (19.9%–32.3%; P = 0.116) in the two groups, respectively. The 3-year overall survival (OS) was 67.4% (95% CI: 59.1%–74.4%) and 61.6% (54.2%–68.1%; P = 0.382), leukemia-free survival (LFS) was 63.4% (95% CI: 55.0%–70.7%) and 58.2% (50.8%–64.9%; P = 0.429), and GVHD-free/relapse-free survival (GRFS) was 51.7% (95% CI: 43.3%–59.5%) and 37.8% (30.9%–44.6%; P = 0.041), respectively, in the HID and MSD groups.Conclusion:HID transplantation has a lower incidence of post-MRD+ than MSD transplantation, suggesting that HID transplantation might have a superior GVL effect than MSD transplantation for Ph– high-risk B-ALL patients.Trial registration:ClinicalTrials.gov: NCT01883180, NCT02673008.

Long-Term Cardiac Effects of Successful Non-Myeloablative HLA-Matched Sibling Transplants in Sickle Cell Disease

INTRODUCTIONCardiopulmonary complications lead to early mortality in adults with sickle cell disease (SCD). We previously showed in a small single-center study that cardiac morphology improves by one year after successful non-myeloablative hematopoietic stem cell transplantation (HSCT). Since cardiac outcomes following HSCT are not well-described, we sought to extend our results to a larger group of SCD patients from the National Institutes of Health (NIH) and University of Illinois Chicago (UIC).METHODSThe majority of patients received alemtuzumab, 300cGy total body irradiation, and sirolimus; 21 also received pentostatin and cyclophosphamide preconditioning. An echocardiogram (echo) and routine laboratory testing were done at baseline before HSCT and at 1 and 2 year time points. Patients with an echo at least one year following HSCT were included.A generalized estimating equation regression model approach was used to evaluate echo and laboratory changes from baseline adjusting for age, gender, and site. A more stringent p-value threshold of 0.005 was used for significance given the large number of outcomes tested. The reported p values compare baseline vs 1 year and 1 year vs 2 year changes.RESULTSThe study population consisted of 88 patients (69 NIH, 19 UIC) who had stable engraftment and were free of dialysis or chronic transfusion therapy. Mean + SD age of patients was 31.5 ± 10.5 years and 36 (41%) are female. Hemoglobin improved significantly in the first year (baseline 8.9 ± 1.5 g/dl, 1 year 12.9 ± 2.3, p < 0.0001), and continued to improve at 2 years (13.6 ± 2.0, p<0.0001). Laboratory results showed improvements in LDH, total bilirubin, and absolute reticulocyte count within the first year after HSCT (data not shown).Body surface area (BSA) was noted to increase significantly in the first year after HSCT (baseline 1.8 ± 0.2 m 2, 1 year 1.9 ± 0.2, p = 0.0002) and then stabilized in the second year (1.9 ± 0.3, p=0.9). Diastolic blood pressure was 66 ± 12 mmHg at baseline and closely followed the BSA, increasing in the first year (73 ± 11, p < 0.0001) and then remaining unchanged in the second year (74 ± 11, p=0.36). Systolic blood pressure (baseline 118 ± 15 mmHg) did not change significantly.The left ventricular size, as measured by the left ventricular end-diastolic volume index (LVEDVI) was elevated at baseline (82.6 ± 21.5 ml/m2), decreased dramatically at 1 year (69.0 ± 14.7, p < 0.0001), and continued to improve significantly at 2 years (63.1 ± 15.0, p < 0.0001, Figure). LV mass index, which is closely related to volume changes, did not change in the first year (baseline 84.9 ± 23.7 g/m 2, 1 year 85.1 ± 20.9, p= 0.72); however, it improved significantly by 2 years (79.2 ± 17.7, p=0.0003). The left atrial size, as measured by the left atrial volume index, also decreased in the first year (baseline 41.4 ± 12.8 ml/m2, 1 year 28.9 ± 8.7, p < 0.0001) with no change in the second year (27.9 ± 8.2, p=0.05). Diastolic filling parameters, which are independent risk markers of mortality, were seen to parallel the volume changes with baseline E/A ratio decreasing in the first year after HSCT (baseline 1.6 ± 0.6, 1 year 1.4 ± 0.4, p < 0.0001) and then remaining unchanged at 2 years (1.4 ± 0.5, p=0.09).Tricuspid regurgitation velocity (TRV), which is also a well-known early mortality risk marker in SCD, decreased significantly in the first year (baseline 2.5 ± 0.4 m/s, 1 year 2.4 ± 0.3, p = 0.002), and suggested a trend towards improvement at 2 years (2.3 ± 0.3, p=0.01). In 37 patients with a high-risk TRV ≥2.5 m/s, there was a significant decrease in the first year (baseline 2.9 ± 0.3, 1 year 2.5 ± 0.3, p < 0.0001) and then no change at 2 years (2.4 ± 0.3, p=0.05)CONCLUSIONOur findings from two independent centers demonstrate significant improvements in cardiac size, mass, diastolic function, and TRV after non-myeloablative HSCT. Volume overload secondary to anemia is responsible for cardiac remodeling in SCD, and as the anemia resolves and high flow rates decrease following HSCT, many of the cardiac changes also reverse. LV volume decreased significantly in the first year, and these improvements, along with decreased LV mass index, continued in the second year. 55% of patients with a high-risk TRV normalized their TRV at 2 years. As diastolic dysfunction and TRV have both been associated with early mortality in adults with SCD, our results suggest that successful HSCT may impact survival. A larger multi-center study with longer follow-up is indicated. [Display omitted] DisclosuresRondelli: Vertex: Membership on an entity's Board of Directors or advisory committees. Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Autologous Stem Cells as Backup for Patients Undergoing Allogeneic Related Transplant for Thalassemia Major.

Abstract 4539Autologous backup of harvested stem cells from patients with Beta thalassemia major, undergoing allogeneic HLA matched sibling transplantation, in order to rescue the patient in the event of graft failure, has been practiced in some transplant centers in the world. From February 2007 we instituted a program of harvesting and cryopreserving autologous bone marrow for all patients undergoing transplant for thalassemia at our center and this abstract is a report on 62 patients for whom this was done over the past 26 months till June 2009. Since most of the patients were below 10 years a bone marrow harvest was performed under general anesthesia. The harvest was depleted of red cells by gravity sedimentation using hydroxyethyl starch, plasma depleted and cryopreserved using 10% dimethyl sulfoxide and stored at -18-degC in the vapor phase of a liquid nitrogen storage system. The mean volume of the product before freezing was 180 ml. The median CD34 cell dose was 8.35 × 106 cells/kg (range 0.6 to 24.6 × 106 cells/kg).During this 26 month period there was one early rejection, after initial engraftment, without autologous recovery with the patient being critically ill and febrile. Autologous stem cells were re-infused on day + 90 when the ANC was 0. However there was progressive deterioration in respiratory function and the patient died on day+92 with disseminated pulmonary aspergillosis. It is extremely difficult to decide when to re-infuse autologous stem cells in a patient who is sick post transplant and may not engraft. There was only one other rejection in this cohort of 62 patients but this patient had spontaneous recovery of autologous hematopoiesis and did not require intervention.The total cost of harvesting autologous stem cells under anesthesia and Cryopreservation, at this center is approximately $ 1600 and this represents 10% of the total cost of an allogeneic stem cell transplant. In this cohort of 62 patients, cryopreserved stem cells were used in only one patient without preventing mortality. The increased cost, manpower and time required for this procedure needs further evaluation and also the criteria on which autologous stem cells are to be re-infused needs to be established. Disclosures:No relevant conflicts of interest to declare.

Favorable Outcomes after Single Cord Blood Transplantation for Patients with High-Risk Hematologic Diseases: A Single-Institute Retrospective Analysis

The donor selection algorithm for cord blood (CB) with regards to matched related and unrelated donors has not been fully investigated. To assess the potential of CB transplantation (CBT) in patients with hematologic malignancies, especially for high-risk patients, we performed a single-institute retrospective analysis and compared the clinical outcomes of CBT with those of HLA-matched sibling and unrelated donor transplantation. We included 394 patients aged 16 years and older with hematologic diseases who received their first allogeneic hematopoietic cell transplantation between 1990 and 2018 at Kyoto University Hospital. These included 394 recipients of single unrelated cord blood units (UCB, n=108), HLA-matched sibling donors (MSDs, n=143), or HLA-matched unrelated donors (MUDs, n=143). There was no significant difference in relapse-free survival (RFS) between UCB, MSD, and MUD recipients (P=.975). However, we found a significant interaction between transplant year and CBT outcomes (P=.010), with significantly better outcomes observed in the more recent years. Furthermore, we found that CBT showed better RFS than matched donor transplantation (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.30 to 0.84). This impact was more prominent in high-risk patients (HR, 0.35; 95% CI, 0.16 to 0.77), with lower relapse rates (HR, 0.25; 95% CI, 0.11 to 0.54), and comparable non-relapse mortality (NRM) compared to matched donor transplantation. Extensive chronic graft-versus-host disease was less frequently observed in CBT (HR, 0.58; 95% CI, 0.26 to 1.28). CBT associated with favorable outcomes, particularly in high-risk patients, with good RFS and low relapse rates without an increase in NRM in the single-institute study. Although the findings should be externally validated, CBT might serve as a reasonable donor choice, particularly in high-risk patients.

Comparison of HLA-matched sibling and unrelated donor transplantation in adult patients with acquired severe aplastic anemia.

The recent improvements in the outcomes of severe aplastic anemia (SAA) patients who received allogeneic stem cell transplantation (SCT) from unrelated donors (URD) suggest the possibility of its alternative first-line treatment. To address this issue, results of adult SAA patients receiving allogeneic SCT were compared between the following three donor-type groups: 8/8-matched sibling (MSD; n = 153), 8/8 well-matched unrelated (WM-URD; n = 72), and 6-7/8 partially matched unrelated (PM-URD; n = 33). Proportion of patients who experienced immunosuppressive treatment failures was significantly higher in the URD groups than in the MSD group (P< 0.01). The incidences of graft failure and transplant-related mortality, and graft-vs.-host disease-free, failure-free survival rates of the MSD, WM-URD, and PM-URD groups were 14.6, 0, and 0% (P< 0.01); 6.1, 10.3, and 21.7% (P= 0.03); and 76.7, 55.5, and 51.5% (P< 0.01), respectively. The overall survival (OS) rate of the MSD group (93.9%) was higher than that of the PM-URD (78.3%; P < 0.01) group, but not to that of the WM-URD (86.2%; P= 0.18) group. Our study showed comparable OS between the MSD group and WM-URD group, which suggest that the URD-SCT can be used as a first-line treatment for adult SAA patients with WM-URD.

A Machine Learning Approach Deciphers the Effects of Immune Parameters on Clinical Outcomes after HLA-Haploidentical and HLA-Matched Allogeneic Bone Marrow Transplantation with Posttransplant Cyclophosphamide

Background We previously demonstrated comparable immune reconstitution after HLA-matched sibling (MSD), HLA-matched unrelated (MUD), and HLA-haploidentical (haplo) bone marrow transplantation (BMT) with posttransplant cyclophosphamide (PTCy). Here, we use machine learning algorithms to identify predictive immunologic variables, providing insight for future translational interventions. Methods We assessed 11 pre-transplant factors, 22 immune subsets, and 7 serum markers at day 28 and day 56 post-BMT in 70 patients who engrafted after myeloablative conditioned (MAC) haplo BMT with PTCy (50mg/kg on days +3 and +4), mycophenolate mofetil (days +5-35), and tacrolimus (days +5-180) and 74 patients who engrafted after MAC HLA-matched BMT with PTCy (50mg/kg on days +3 and +4). Classification and regression tree machine based learning with nodal selection was applied to detect risk groups for four outcomes: overall survival (OS), progression-free survival (PFS), acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD). Results When compared with cytomegalovirus (CMV) seronegative recipients, CMV seropositive recipients had higher CD3+ T cells, effector memory (EM) CD4+ T cells, T effector memory expressing RA (TEMRA) CD4+ T cells, CD8+ T cells, EM CD8+ T cells, and TEMRA CD8+ T cells at early time points after both BMT platforms (not shown). Pre-BMT disease status and natural killer (NK) cell count at day 28 emerged as predictive variables for survival. Two-year OS and PFS for patients in complete remission (CR) with NK cells >54 cells/µL were 98% and 89%, in CR with NK cells 55 cells/µL, the CuI of aGVHD was 18% in those with CXCL-9 Conclusion Machine learning using immune cellular and soluble markers can be successfully applied to identify risk factors for BMT outcomes. High CD4+ counts and CXCL-9 levels at day 28 predicted aGVHD and high reg3α at day 56 predicted cGVHD. Both CXCL-9 and reg3α represent potential therapeutic targets. Finally, disease status and NK cell counts at day 28 predicted OS and PFS. These data support research to determine what influences NK cell recovery as well as to investigate NK cell therapy for recipients with active disease or for those with poor early NK cell reconstitution.

Superior Graft-Versus-Leukemia Effect in Haploidentical Transplantation Compared with HLA-Matched Sibling Transplantation for High-Risk Acute Myeloid Leukemia in First Complete Remission: A Prospective Multicentre Cohort Study

This study aimed to investigate graft-versus-leukemia (GVL) of haploidentical donor (HID) compared with HLA-matched sibling donor (MSD) for high-risk acute myeloid leukemia (H-AML) in first complete remission (CR1). One hundred and eighty-nine patients with H-AML in CR1 were enrolled in this multicentre prospective cohort study. Patients were assigned to groups transplanted with HID (n=83) or MSD (n=106) based on donor availability (biological randomization). The primary endpoint was the incidence of MRD positivity post-transplantation (post-MRD+). All post-MRD+ patients received preemptive interventions. The cumulative incidences of post-MRD+ were 18% and 42% in HID and MSD groups, respectively, (p&lt;.001). Fifty-two patients received preemptive DLI, including 13 (16%) in HID and 39 cases (37%) in MSD groups (p=.001). Among HID and MSD groups, the 3-year cumulative incidence of relapse were 14% and 24% (p=0.101); the 3-year cumulative incidence of treatment-related mortality were 15% and 10% (p=0.368); the 3-year overall survival rates were 72% and 68% (p=0.687); the 3-year disease-free-survival were 71% and 66% (p=0.579); the 3-year graft-versus-host disease and relapse free survival were 63% and 43% (p=0.035), respectively. HID has a stronger GVL than MSD in H-AML patients. HID transplantation as post-remission therapy should be recommended as one of the optimal choices for H-AML in CR1. Disclosures No relevant conflicts of interest to declare.

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

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

Decitabine plus CLAG chemotherapy as a bridge to haploidentical transplantation in the setting of acute myeloid leukemia relapse after HLA-matched sibling transplantation: a case report

BackgroundPatients with relapsed/refractory acute myeloid leukemia after hematopoietic stem cell transplantation (HSCT) have a poor prognosis, with a 2-year survival rate of 14%. The optimal treatment for these patients remains unclear. To treat these patients, we designed a new salvage regimen consisting of decitabine, cladribine, cytarabine, and granulocyte-stimulating factor (D-CLAG).Case presentationHere, we describe a case of acute monocytic leukemia with a complex karyotype in a 38-year-old female patient who relapsed after her first HSCT, which was performed using a matched sibling donor. The patient did not respond to standard induction chemotherapy and subsequently achieved complete remission with the D-CLAG regimen. No severe hematological or extramedullary toxicity was observed. Subsequently, the patient received a second D-CLAG regimen as a bridge therapy and directly underwent haploidentical related HSCT. Following HSCT, the marrow showed complete hematologic and cytogenetic remission. Currently, 1 year after transplantation, the patient’s general condition remains good.ConclusionsThis case suggests that the D-CLAG regimen can be an option for reinduction in relapsed refractory AML patients as a bridge to transplantation. Nevertheless, further research will be required in the future as this report describes only a single case.

Processing of G-CSF Mobilized Peripheral Blood Hematopoietic Progenitor Cells (PB-HPC) from Matched- Related or Unrelated Donors Undergoing CD34 Enrichment with T Cell Addback in Children, Adolescents and Adults with Malignant and Nonmalignant Diseases: Rapid Engraftment, Immune Cell Reconstitution and Sustained Donor Chimerism

Sixty to seventy percent of patients undergoing HLA identical transplants will develop grade II-IV acute GVHD, despite using prophylactic immunosuppressants. Several studies have demonstrated that manipulation utilizing ex-vivo CD34+ positively selected grafts result in 4-5 log T-cell depletion with limited T-cell add back follow with early engraftment and decreased aGVHD (Silva et al, Blood Journal, 2015 & Chakrabarti et al, BMT, 2003). We previously demonstrated the safety and efficiency of CD34+ enriched cells with 2 × 105 CD3 (MNC)/kg add back in pediatric SCD patients resulting in rapid engraftment, donor chimerism, and low incidence of aGVHD (Geyer/Cairo et al, BJH, 2012). Utilizing CD34+ cell selection, children, adolescents, and adults with a matched or partially matched family donor or matched unrelated donors allogeneic PB-HPC transplant can safely receive and tolerate with a low incidence of serious (Grade III/IV) acute and chronic GVHD. Patients received CD34+ enriched products processed by using the CliniMACS CD34+ Reagent System (Miltenyi Biotec, Bergisch Gladbach, Germany). The CD34+ enriched HPC product was either a fresh infusion or cryopreserved and stored until time of transplantation. A target of 5 × 106 CD34+enriched/kg recipient weight with a T cell add back of 2 × 105 CD3+/kg (MNC) was infused. Sixteen patients underwent BMT with median age of 55 years (23 months to 71 years). Patients' disease status was as follows: complete remission (CR) 2 in four AML patients, CR1 in 9 AML patients, Lymphohistiocytosis (n=1), Macrophage Activating Syndrome (n=1), CR2 in one Non-Hodgkins Lymphoma patient. Nine patients received 10/10 HLA-matched unrelated donor BMT, two 9/10 HLA-matched unrelated donors, five had 6/6 HLA-matched sibling transplant. PB-HPC products contained 0.59 × 1010 CD3/kg (±0.23), and 6.77 × 106 CD34/kg (±1.27). After CD34 enrichment, the PB-HPC CD34% recovery was 73.1±3.08% with a log T cell depletion of 4.9 (±0.11). The target transplant dose per patient was 5 × 106 CD34 enriched/kg. Sixteen and patients had myeloid and 13 patients had platelet engraftment with a median of 11.5 days and 16 days, respectively (Fig. 1a and Fig. 1b). Two patients died prior to platelet engraftment one due to multi-organ system failure following septic shock and the other patient due to refractory AML. One patient died after myeloid and platelet engraftment secondary to disease progression. Early and late peripheral blood chimerism were ≥ 98.4% at 19.9 days (±12) and 92.5% at 180 days (n=4). The probability of grade II-IV aGVHD was 20% (CI95: 0.1-66.9) (Fig 2). One patient had grade II skin aGVHD and one patient had grade II gut aGVHD. No patient had cGVHD. This study demonstrates the safety and efficiency of CD34+ enriched PB-HPC products with T-cell addback in AlloSCT recipients with a low probability of acute GVHD.

Donor Lymphocyte Infusion from G-CSF-Primed, Unmanipulated Whole Blood Is Safe and Improves Chimerism in HLA-Matched and Haploidentical Transplantation

Introduction Donor lymphocyte infusion (DLI) is a useful therapy for mixed chimerism (MC) and measurable residual disease (MRD) after allogeneic transplantation (HSCT). Multiple DLI products can be obtained through apheresis and cryopreservation, but their costs can be prohibitive in developing countries. T-cells in whole blood units can reach ≥1 × 106/kg in healthy donors and are increased after G-CSF exposure. The ideal CD3+ cell dose remains undefined. Objectives We aim to assess the safety and efficacy of G-CSF-primed whole blood units (WB-DLI) in peripheral blood HLA-matched sibling (MSD) and haploidentical (Haplo) transplant recipients. Methods Adults who received WB-DLI at any time after HSCT due to relapse, MRD, MC or poor graft function were included. Patients with active graft-versus-host disease (GVHD) were excluded. Donors received filgrastim 5 μg/kg QD (days 1-3) followed by a 450 mL whole blood draw on day 4 with crossmatching and lymphocyte quantification. For patients with major/bidirectional ABO mismatch without group switch or a mixed field reaction, a reactive major crossmatch was an absolute contraindication. WB-DLI was infused fresh and unmanipulated in an outpatient basis. Concurrent chemotherapy was allowed. Disease and chimerism were assessed on day 30 and 60, respectively. GVHD prophylaxis included oral cyclosporine/tacrolimus tapered in 60 days. Results Fourteen patients received a single WB-DLI, median age was 32 years (range, 16-67), 50% were women. Most common diagnoses were ALL, (n=5) and AML (n=5), followed by MDS (n=2), NHL (n=1) and CML (n=1). Nine had were Haplo grafts, while 4 were MSD. Indication for WB-DLI was relapse in 6 patients, 3 had MRD, 4 MC and 1 had poor graft function. Median chimerism pre-WB-DLI was 72% (range, 38-100%). Median mononuclear cell count obtained was 32 × 10x6/kg (range, 9-74), while median CD3+ cell count was 6.7 × 106/Kg (range, 5.2-19). No immediate severe adverse effects were observed. Febrile non-hemolytic reaction occurred in n=4. No complications were observed in n=4 ABO mismatch cases. Overall 50% responded; chimerism improved in 50%, with a median increase of 28% (range, 9-53%). Median post-DLI chimerism was 92.5% (range, 20-100). Regarding patients treated for relapse or MRD 4/9 responded (33%). Overall 8/14 patients relapsed (57%) with 12-month progression free survival of 27.5% which was significantly lower in relapsed/MRD patients (log rank test p=0.042). Overall survival at 12 months was estimated at 61.2%. Three developed aGVHD, 2 grade III/IV in a median of 13 days (range, 7-38). Four died due to relapse. Median follow-up was 5 months (0.6-20.1 months). The cost of performing WB-DLI was $350 USD per unit. Conclusions DLI obtained from GCSF-primed whole-blood is safe and affordable. It improves mixed chimerism, while it is less effective for overt relapse, similarly to DLI obtained through standard methods.

Related and Unrelated Donor Transplantation for β Thalassemia Major: Results of an International Survey

▪We studied 1110 children, adolescents and young adults with β thalassemia major transplanted with grafts from HLA-matched relative (n=677; 61%), HLA-mismatched relative (n=78; 7%), HLA-matched unrelated (n=252; 23%) and HLA-mismatched unrelated (n=103; 9%) donors in 2000 - 2016. The median age at transplantation was 6 years (range <1 - 25). Eight-five percent received ≥20 transfusions and 88% were reported as “inadequately” chelated. Most patients (73%) had hepatomegaly (2 cm or greater below the right costal margin) and 50% reported serum ferritin ≥2500 ng/mL. The Pesaro risk class could be assigned for only 526 (47%) of transplantations: Class I (39%), Class II (8%) and Class III (54%). Liver biopsies are not routinely performed in China. All patients received a myeloablative transplant conditioning regimen; 34% received busulfan (Bu; IV 8.4 - 13.2 mg/kg) + cyclophosphamide (Cy; 100-120 mg/kg) + thiotepa (TT; 5 mg/kg) + fludarabine (FLU; 200 mg/m2), 23%, Bu (IV 11-16 mg/kg) + Cy (100-120 mg/kg) + FLU (200 mg/m2), 22%, Bu (PO or IV 16 mg/kg) + Cy (200 mg/kg), 15%, treosulfan (42 mg/m2) + TT (8 mg/kg) + FLU (120 mg/m2) and the remaining 5%, Bu (PO or IV 12 or 16 mg/kg) or melphalan (140 mg/m2) + FLU (150 - 180 mg/m2) ± TT (8-10 mg/kg). Bu dosing was based on pharmacokinetic studies. In vivo T-cell depletion (anti-thymocyte globulin), graft-versus-host disease (GVHD) prophylaxis and graft type were confounded with transplant conditioning regimen. Ninety percent of transplants were in 2006-2016. The median follow-up was 48 months (range 3 - 193). The day-28 incidence of neutrophil recovery in patients aged ≤6 years, 7-15 years and 16-25 years were 92%, 93%, and 82%, respectively, p=0.28. The corresponding day-100 incidence of platelet recovery were 93%, 90%, and 70%, respectively, p<0.001. The 5-year incidence of graft failure was higher for patients aged 16-25 years at 23% compared to 8% and 10% for patients aged ≤6 and 7-15 years (p=0.01). Risk factors associated with overall mortality and treatment failure (graft failure or death from any cause) are shown in Table 1. Overall survival and disease-free survival (alive with sustained engraftment) were highest in children aged ≤6 years and received grafts from an HLA-matched sibling or HLA-matched unrelated donor. The 5-year probabilities of overall survival for patients aged ≤6 years, 7-15 years and 16-25 years were 91%, 83% and 55%, respectively, p<0.001. The corresponding probabilities for disease-free survival were 87%, 79% and 55%, p<0.001 (Figure 1). In the subset of patients for whom Pesaro risk class could be assigned, mortality and treatment failure were higher for Class II and Class III compared to Class I (Table 1). We tested for an effect of transplant center on survival and found none. Risks for acute grade II-IV GVHD were higher after HLA-mismatched related (hazard ratio [HR] 3.04, p<0.001), HLA-matched unrelated (HR 3.35, p<0.001) and HLA-mismatched unrelated (HR 2.21, p=0.003) compared to HLA-matched sibling transplants. Similarly, chronic GVHD risks were also higher after HLA-mismatched related (HR 2.64, p=0.002), HLA-matched unrelated (HR 2.13, p=0.018) and HLA-mismatched unrelated (HR 4.25, p<0.001) compared to HLA-matched sibling transplants. Nevertheless, mortality and treatment failure risks did not differ after HLA-matched sibling and HLA-matched unrelated donor transplants. In conclusion, transplantation for β thalassemia major should be offered early (aged 6 years or younger) from an HLA-matched sibling or an HLA-matched unrelated donor. Mismatched related donor transplants were associated with higher treatment failure and overall mortality. These data suggest cautious use of the following conditioning regimens: Bu + Cy, treosulfan + TT + FLU and Bu or melphalan ± TT ± FLU although identifying an optimal conditioning regimen(s) are best studied in the setting of carefully controlled clinical trials. [Display omitted] DisclosuresDvorak:Jazz Pharmaceuticals: Consultancy; Chimerix, Inc.: Membership on an entity's Board of Directors or advisory committees. Shenoy:Novartis, Vertex, Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

Allogeneic Hematopoietic Cell Transplantation in Patients Aged 50Years or Older with Severe Aplastic Anemia

We report on 499 patients with severe aplastic anemia aged ≥ 50years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (n = 275, 55%) or HLA-matched (8/8) unrelated donors (n = 187, 37%) between 2005 and 2016. The median age at HCT was 57.8 years; 16% of patients were 65 to 77years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90% (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.03 to 1.92; P = .03) and after unrelated donor transplantation (HR, 1.47; 95% CI, 1 to 2.16; P = .05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66% (range, 57% to 75%) and 57% (range, 47% to 76%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57% (range, 48% to 67%) and 48% (range, 36% to 59%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65years or older (subdistribution HR [sHR], 1.7; 95% confidence interval, 1.07 to 2.72; P = .026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI) + methotrexate (sHR, .52; 95% CI, .33 to .81; P = .004) and CNI alone or with other agents (sHR, .27; 95% CI, .14 to .53; P < .001) compared with CNI + mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes.

P015 Bone marrow donor selection in the presence of both allogeneic and syngeneic donors

Syngeneic transplants provide an interesting dilemma with respect to donor selection. The risk of relapse is higher for patients with AML undergoing syngeneic transplant vs. HLA-matched sibling transplant, however, rates of graft versus host disease and transplant related mortality have historically been lower with syngeneic transplants. Thus, HLA -matched sibling donors are preferred to identical twin donors for patients undergoing transplant for malignant diseases (ie. AML) to optimize the impact of graft vs. leukemia (GvL) whereas identical twin donors are ideal for non-malignant disorders. We present a patient with AML who had both an HLA matched sibling donor as well as an identical twin. He was initially transplanted with the HLA matched sibling donor successfully however, at 6 months post transplant he developed severe neutropenia (ANC = 0). Chimerism studies revealed 95% DNA from the related donor T cells at this time. The cause of his neutropenia was autoimmune in nature and refractory to multiple immunosuppressive medications and therefore he underwent a second transplant this time using his identical twin as the donor. The patient’s neutrophils engrafted and he has undergone a complete recovery post transplant. Chimerism studies after the second transplant reveal that 85% of the DNA is from the second donor’s T cells. Typically, chimerism studies with syngeneic transplant are not helpful as the patient and donor are identical. However in this case, chimerism studies were possible to determine the engraftment of the initial related donor to the patient/twin. This case illustrates that optimal donor selection depends on disease when an identical twin and an HLA matched sibling donor are available. It also showcases the interesting results of chimerism testing in a patient who has received both an allogeneic and a syngeneic transplant.