HLA-haploidentical Stem Cell Transplantation Research Articles

HLA-haploidentical stem cell transplantation in children with inherited bone marrow failure syndromes: A retrospective analysis on behalf of EBMT severe aplastic Anemia and pediatric diseases working parties.

Haploidentical stem cell transplantation (haplo-SCT) represents the main alternative for children with inherited bone marrow failure syndrome (I-BMF) lacking a matched donor. This retrospective study, conducted on behalf of the EBMT SAAWP and PDWP, aims to report the current outcomes of haplo-SCT in I-BMFs, comparing the different in vivo and ex vivo T-cell depletion approaches. One hundred and sixty-two I-BMF patients who underwent haplo-SCT (median age 7.4 years) have been registered. Fanconi Anemia was the most represented diagnosis (70.1%). Based on different T-cell depletion (TCD) approaches, four categories were identified: (1) TCRαβ+/CD19+-depletion (43.8%); (2) T-repleted with post-transplant Cyclophosphamide (PTCy, 34.0%); (3) In-vivo T-depletion with ATG/alemtuzumab (14.8%); (4) CD34+ positive selection (7.4%). The cumulative incidences (CI) of neutrophil and platelet engraftment were 84% and 76% respectively, while that of primary and secondary graft failure was 10% and 8% respectively. The 100-day CI of acute GvHD grade III-IV(95% CI) was 13%, while the 24-month CI of extensive chronic GvHD was 4%. After a median follow-up of 43.4 months, the 2-year overall survival(OS) and GvHD/Rejection-free Survival (GRFS) probabilities are 67% and 53%, respectively. The TCR CD3+αβ+/CD19+ depletion group showed a significantly lower incidence of both acute and chronic GvHD and higher OS (79%; p0.013) and GRFS (71%; p < .001), while no significant differences in outcomes have been observed by different diagnosis and conditioning regimens. This large retrospective study supports the safety and feasibility of haplo-SCT in I-BMF patients. TCRαβ+/CD19+ depletion offers higher chances of patients' survival, with a significantly lower risk of severe a- and c-GvHD in I-BMFs compared to other platforms.

Prediction model for EBV infection following HLA haploidentical matched hematopoietic stem cell transplantation

AimsAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for hematological malignancies. However, viral infections, particularly EBV infection, frequently occur following allo-HSCT and can result in multi-tissue and organ damage. Due to the lack of effective antiviral drugs, these infections can even progress to post-transplant lymphoproliferative disorders (PTLD), thereby impacting the prognosis. In light of this, our objective is to develop a prediction model for EBV infection following allo-HSCT.MethodsA total of 466 patients who underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) between September 2019 and December 2020 were included in this study. The patients were divided into a development cohort and a validation cohort based on the timing of their transplantation. Our aim was to develop and validate a grading scale using these cohorts to predict the risk of EBV infection within the first year after haplo-HSCT. Additionally, single-cell RNA sequencing (sc-RNAseq) data from the bone marrow of healthy donors were utilized to assess the impact of age on immune cells and viral infection.ResultsIn the multivariate logistic regression model, four predictors were retained: donor age, female-to-male transplant, graft MNC (mononuclear cell) dose, and CD8 dose. Based on these predictors, an EBV reactivation predicting score system was constructed. The scoring system demonstrated good calibration in both the derivation and validation cohorts, as confirmed by the Hosmer–Lemeshow test (p > 0.05). The scoring system also exhibited favorable discriminative ability, as indicated by the C statistics of 0.72 in the derivation cohort and 0.60 in the validation cohort. Furthermore, the clinical efficacy of the scoring system was evaluated using Kaplan–Meier curves based on risk ratings. The results showed significant differences in EBV reactivation rates between different risk groups, with p-values less than 0.001 in both the derivation and validation cohorts, indicating robust clinical utility. The analysis of sc-RNAseq data from the bone marrow of healthy donors revealed that older age had a profound impact on the quantity and quality of immune subsets. Functional enrichment analysis highlighted that older age was associated with a higher risk of infection. Specifically, CD8 + T cells from older individuals showed enrichment in the pathway of “viral carcinogenesis”, while older CD14 + monocytes exhibited enrichment in the pathway of "regulation of viral entry into host cell." These findings suggest that older age may contribute to an increased susceptibility to viral infections, as evidenced by the altered immune profiles observed in the sc-RNAseq data.ConclusionOverall, these results demonstrate the development and validation of an effective scoring system for predicting EBV reactivation after haplo-HSCT, and provide insights into the impact of age on immune subsets and viral infection susceptibility based on sc-RNAseq analysis of healthy donors' bone marrow.

HLA haploidentical stem cell transplantation from HLA homozygous donors to HLA heterozygous donors may have lower survival rates than haploidentical transplantation from HLA heterozygous donors to HLA heterozygous donors: a retrospective nationwide analysis.

In HLA haploidentical stem cell transplantation, patients and donors usually share one HLA haplotype and have one different HLA haplotype (hetero-to-hetero). However, there are rare cases of transplantation from HLA homozygous donors to heterozygous recipients (homo-to-hetero), resulting in mismatches only in the graft-versus-host direction. We previously reported that homo-to-hetero transplants have a lower survival rate in a mouse model than hetero-to-hetero transplants due to stronger graft-versus-host disease (GVHD) but inferior graft-versus-leukemia effect. To examine whether homo-to-hetero transplant effects also occur in humans, we retrospectively compared the results of 59 homo-to-hetero and 4,539 hetero-to-hetero cases in the Japanese transplant registry data. The results showed no statistical difference between the homo-to-hetero and hetero-to-hetero groups in the cumulative incidences of neutrophil engraftment (83.1% vs 89.0%), acute GVHD II-IV (36.8% vs 38.8%), III-IV (16.8% vs 17.4%), chronic GVHD (32.7% vs 30.7%), relapse (52.9% vs 49.0%), and non-relapse mortality (31.6% vs 28.2%). In contrast, overall survival was significantly lower in the homo-to-hetero group than in the hetero-to-hetero group (12.6% vs 26.2%, p = 0.0308). The inferior effect of homo-to-hetero transplantation on overall survival remained significant in multivariate analyses.

New era of GVHD prophylaxis using posttransplant cyclophosphamide

Use of posttransplant cyclophosphamide (PTCy) for the prophylaxis of graft-versus-host disease (GVHD) has revolutionized the field of HLA-haploidentical stem cell transplantation, which was previously considered high-risk and only feasible in specialized centers. The rapid adoption of PTCy is attributed not only to its superior efficacy in suppressing GVHD but also to its affordability and the lack of need for specialized techniques or equipment to administer it. Recently, PTCy has gained attention for its potential effectiveness in GVHD prophylaxis beyond HLA-haploidentical stem cell transplantation. In a phase III trial (BMT CTN 1703 trial) in patients undergoing allogeneic HLA-matched stem cell transplantation with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly better among those who received PTCy-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. In Japan, a phase II clinical trial that investigated PTCy for GVHD prophylaxis following HLA-matched or 1-2 allele mismatched peripheral blood stem cell transplantation confirmed the efficacy and safety of this approach. Effective suppression of GVHD using PTCy is expected to enhance the safety of allogeneic transplantation, potentially improving transplant outcomes and offering hope for better patient care in the field of transplantation.

CR1 Favors PTCy-haplo over UCB in Allogeneic Stem Cell Transplantation for Adult Patients with AL

[Introduction] HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCB) are alternative to HLA-matched hematopoietic stem cell transplantation (HSCT). However, advantage of PTCy-haplo versus UCB has not been determined in patients with acute lymphoblastic leukemia (ALL). Thus, we compared post-HSCT outcomes of PTCy-haplo and UCB in adult patients with ALL to determine patient subgroups who benefit from PTCy-haplo. [Methods] We analyzed data on adult patients (≥16 years) with ALL who underwent HSCT with PTCy-haplo or single-unit UCB between January 2013 and December 2021, using the Japanese nationwide registry database. Endpoints of the analysis included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse, non-relapse mortality (NRM), engraftments, acute and chronic graft-versus-host disease (GVHD), and infections. In addition to multivariate analysis, propensity score matching was performed as a sensitivity analysis. [Results] We analyzed 1999 patients (PTCy-haplo, 330; UCB, 1669). Median age at HSCT was 44.5 years (range, 16-73) in PTCy-haplo and 45 years (range, 16-74) in UCB group. The proportion of patients who underwent HSCT in the first complete remission (CR1) (PTCy-haplo, 50.3%; UCB, 48.8%) and median time from diagnosis to HSCT (PTCy-haplo, 7.8 months; UCB, 7.7 months) were comparable between the groups. Regarding conditioning, the proportion of those who received myeloablative conditioning (PTCy-haplo, 50.6%; UCB, 54.8%), or conditioning with total body irradiation (PTCy-haplo, 82.4%; UCB, 79.3%) were comparable between the groups. Multivariate analyses showed that PTCy-haplo recipients had comparable 3-year OS (54.1% vs. 52.3%; adjusted hazard ratio [aHR], 0.93; p = 0.51) and DFS (49.7% vs. 47.1%; aHR, 1.06; p = 0.60) with UCB recipients. PTCy-haplo recipients had a significantly higher 3-year relapse rate (32.2% vs. 26.4%; aHR, 1.47; p = 0.01), but had a significantly lower 3 -year NRM (18.1% vs. 26.5%; aHR, 0.70; p = 0.03) as compared to UCB along with significantly faster neutrophil (median, 16 days vs. 20 days) and platelet (median, 30 days vs. 42 days) engraftments, and lower incidence of viral, fungal and bacterial infections. There was no significant difference in cumulative incidence of acute GVHD (30.9% vs. 36.4%, grade II-IV at 100 days; p = 0.15), or chronic GVHD (22.5% vs. 20.9% at 3 years; p = 0.85) between the two groups. These comparable OS and DFS between the two groups were confirmed after minimizing differences in patient characteristics with propensity score matching analysis (Figure 1A). Then, to identify patient subgroups who benefit from PTCy-haplo rather than UCB transplant, we performed subgroup analyses of OS. Significantly favorable effects of PTCy-haplo over UCB were observed in patients with CR1 at HSCT (HR, 0.66; p = 0.03). Indeed, propensity score matching analysis showed that PTCy-haplo recipients had a significantly higher 3-year OS (76.4% vs. 67.6%; HR, 0.57; p = 0.01) and DFS (70.5% vs. 60.6%; HR, 0.66; p = 0.03) than UCB recipients, along with a significantly lower NRM (12.9% vs. 26.3%; HR, 0.39; p &amp;lt; 0.01), and a comparable relapse rate (16.6% vs. 13.1%; HR, 1.41; p = 0.25) with UCB. These results suggest that the low NRM in PTCy-haplo transplant outweighs potential concerns of relapse among patients transplanted in CR1 (Figure 1B). By contrast, in patients with ≥ 2 nd CR or non-CR at HSCT, survival benefits of PTCy-haplo were not observed. [Conclusions] Our results suggest that while both PTCy-haplo and UCB are suitable alternative donor sources for adult ALL patients without HLA-matched donors, in patients with CR1, selection of PTCy-haplo rather than UCB improves post-transplant prognosis.

HLA-haploidentical stem cell transplantation

HLA-haploidentical stem cell transplantations using posttransplant cyclophosphamide (PTCy-haplo) rapidly increased worldwide. In Japan, the number of HLA-haploidentical stem cell transplantation cases exceeded related HLA-matched transplants in 2020. Recent retrospective studies using Japanese registry data have reported comparable transplantation outcomes between PTCy-haplo and HLA-matched unrelated and cord blood transplantations. PTCy-haplo was initially developed in the bone marrow transplantation setting after non-myeloablative conditioning but has recently become widely used in peripheral blood stem cell transplantation and myeloablative conditioning. Peripheral blood stem cell transplantation increases the occurrence of graft-versus-host disease but may have more improved transplant outcomes compared with bone marrow transplantation. Other factors, such as the number of infused cluster of differentiation 34-positive cells, donor age, HLA class II mismatch, HLA-B leader, and reduced PTCy dosage, may also contribute to the outcome of PTCy-haplo transplantations. Furthermore, PTCy has been reportedly effective in related/unrelated HLA-matched transplantation and HLA-mismatched unrelated transplantations. A prospective phase II trial using PTCy in patients who underwent HLA-matched and 1-2 allele-mismatched transplantation is ongoing in Japan. Patient enrollment has already been completed, and the results will be revealed soon. Using PTCy to sufficiently reduce the occurrence of graft-versus-host disease will make performing allogeneic transplants with a higher safety level possible.

HLA-Haploidentical Stem Cell Transplantation in Children with Inherited Bone Marrow Failure Syndromes: A Retrospective Analysis on Behalf of EBMT Severe Aplastic Anemia Working Party

INTRODUCTION: HLA-haploidentical stem cell transplantation (HAPLO) has been widely used in the last years in children with an indication to receive an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and lacking a matched donor. The introduction of new, more selective techniques of graft manipulation and in vivo T-cell depletion have improved the outcome of HAPLO in several diseases. Allo-HSCT represents the only well-established cure for the hematological manifestations of inherited bone marrow failure syndromes (I-BMFs), featuring complex molecular pathophysiology resulting in ineffective hematopoiesis and increased risk of progression to myelodysplastic syndrome and acute leukemia. However, data on HAPLO in these diseases are limited. This retrospective study aims to report the current outcomes of HAPLO in the EBMT network in patients with I-BMFs, comparing the different approaches introduced over the years. PATIENTS AND METHODS The study was conducted on behalf of the Severe Aplastic Anemia Working Party of the EBMT. Data were collected from patients who underwent HAPLOs of I-BMFs and registered in the EBMT ProMISe database between 1990-2020 with a diagnosi. Clinical and biological information about the disease and details on transplant procedures and outcomes were collected through a specific case report form distributed to participating EBMT centers. RESULTS Data was collected from 162 patients (53.1% males) affected by I-BMFs undergoing HAPLO in 56 centers. The median age at HAPLO was 7.4 years (IQR 4.9-10.9). Table 1 summarizes the diagnoses and main HSCT details. Most HAPLOs were performed in 2015 (n=125, 77.2%). Based on different T-cell depletion (TCD) approaches, 4 categories were identified: 1) TCRCD3+ or ab+/CD19+depletion performed in 71 transplants (43.8%); 2) T-repleted with post-transplant Cyclophosphamide (PTCy) in 55 (34.0%); 3) in vivo T-depletion approach in 24 (14.8%; 20 ATG, 4 anti-CD52); and 4) CD34+ positive selection in 12 (7.4%). Neutrophil and platelet engraftment occurred on day + 14 (95% CI 13-15), and +18 (95% CI 16-21) respectively. Primary graft rejection was diagnosed in 14 children (10% [5-14%]), while 11 experienced secondary graft failure (8% [3-12%]). The 100-day cumulative incidence of grade II-IV and III-IV acute GvHD (95% CI) was 29 % (22-36) and 13% (8-19), while the 24-month cumulative incidence of chronic GvHD was 11% (6-16%) and that for the extensive form was 4% (1-7%). After a median follow-up of 43.4 months (IQR 32.9- 51), the 2-year overall survival (OS) and GvHD/Rejection-free Survival (GRFS) probability are 67% (60-74%) and 53% (45-61%) respectively (Figure 1). The main causes of death were infections (40.4%), GvHD (28.8 %), other HSCT-related events (28.85 %), and relapse of acute leukemia in 1 patient with malignant transformation (1.9 %). When we analyzed the outcome by the modality of TCD, the TCR CD3+ab+/CD19+ depletion group showed the best OS (79%) and GRFS (71%) that were significantly higher (p 0.013 and p <0.001, respectively) than those observed in the other groups. (Figure 1). The TCR CD3+ab+/CD19+ depletion group also was associated with a lower incidence of acute (15%, vs 46 % PT-Cy, vs 9% CD34+ positive, vs 41% in-vivo TCD; p 0.001) and chronic GvHD (9%, vs 19% PT-Cy, vs 0% CD34+ positive selection vs 0 % in-vivo TCD; p < 0.041). No differences in outcome were observed based on the underlying diagnosis. CONCLUSION This is the largest retrospective study on HAPLO in I-BMFs comparing the main TCD approaches and the long median follow-up of almost 4 years contributes to the reliability of the data reported. The satisfactory outcome supports HAPLO HSCT as a safe and effective alternative for patients lacking a full-matched donor. The most widely adopted approaches are TCR CD3+ab+/CD19+ depletion and PT-Cy. PT-Cy is largely used because of its easy accessibility, but for the time being, the TCR CD3+ab+/CD19+ depletion platform offers the highest OS and GRFS and the lower incidence of both acute and chronic GvHD in I-BMFs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Brentuximab in Children, Adolescent and Young Adults with Relapsed/Refractory Anaplastic Large Cell Lymphoma

Background: Anaplastic Large Cell Lymphoma (ALCL) is an aggressive malignancy characterized by strong expression of CD30. Multi-agent chemotherapy cures 65-90% of newly diagnosed patients, the rate of relapse approaching 30%. Targeted agents eventually followed by allogeneic stem cell transplantation (SCT) may represent a valuable salvage therapy in patients with relapsed/refractory ALCL. Brentuximab vedotin is a CD30-directed monoclonal antibody-drug conjugate (ADC) that comprises a monoclonal human/murine antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Design and methods: We retrospectively analyzed monocentric data of 20 patients with ALCL treated with Brentuximab from 2.10.2014 to 22.05.2022. Treatment was characterized by the intravenous infusion of 1.8 mg/kg Brentuximab in monotherapy or as part of a polychemotherapy regimen, in children with either relapsed disease or not fully responding to first-line treatment. More in detail, chemotherapy regimens administered in combination with the immunotherapy were: bendamustine, AM and BM blocks (ALCL99 Trial), or AA, BB and CC blocks (LNH97 Trial). Objective response rate (ORR) was assessed through computed tomography (CT)/FDG-PET scans. Results: Eight patients received Brentuximab for incomplete response to first-line treatment (2 of them had haemophagocytic lymphohistiocytosis at diagnosis, and underwent genetic testing that revealed the heterozygous variant c.1336C>T (p.Arg446Trp) in IKBKB gene and the hemizygous variant c.622T>C (p.Ala91Val) in IL2RG gene, respectively). In these patients, Brentuximab was mostly used in combination with the ALCL99 regimen. Three of these 8 patients experienced a subsequent relapse and were re-exposed to the drug after disease recurrence. Fifteen patients received Brentuximab at relapse. Median time between diagnosis and relapse was 10.3 months (range 3.4-34 months). The median number of Brentuximab infusions was 7 (range 2-25). The combination of Brentuximab 1.8 mg/kg/dose on Day 1 and Bendamustine 120 mg/m2/dose on Day 2 and 3, was the principal reinduction regimen in the relapsed cohort, having been infused in 9 patients with a median of 4 cycles (range 2 to 5). This drug combination was very well tolerated and showed a 100% complete response (CR) assessed by CT and FDG-PET scans, allowing to perform allogeneic SCT in all of them. Allogeneic SCT was performed in 15 patients (one of them was the child with haemophagocytic lymphohistiocytosis at diagnosis given Brentuximab during the first-line treatment because of incomplete response), while the remaining child, who had relapsed 34 months after the diagnosis, was treated with Brentuximab monotherapy and remains in CR. Nine patients received HLA-haploidentical SCT, while the remaining 6 were transplanted using either a matched sibling donor (3 patient) or an unrelated volunteer (3 patients) respectively. Sixteen out of the 20 patients (80%) are alive and disease free with a median follow-up of 28.6 months (range 3-78.7). Three patients died due to transplant related causes and 1 patient due to disease progression. Conclusions: Despite the limitations of a limited number of patients analyzed and the retrospective nature of the study, our data suggest that Brentuximab administered either in monotherapy or in combination with chemotherapy is a valuable salvage option and may represent a suitable bridge to allogeneic SCT.

Comparable survival outcomes with haploidentical stem cell transplantation and cord blood transplantation.

HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCBT) are alternative to HLA-matched stem cell transplantation. We conducted a matched-pair analysis of PTCy-haplo and UCBT using the Japanese registry data. We identified 136 patients aged between 16 and 69 years who received PTCy-haplo as their first transplantation for acute leukemia or myelodysplastic syndromes. Control group included 408 UCBT recipients selected to match the PTCy-haplo group. Overall and relapse-free survival probabilities at 2 years were comparable between the PTCy-haplo and UCBT groups: 55% vs. 53% for overall survival (p = 0.46), and 47% vs. 48% for relapse-free survival (p = 0.79), respectively. The cumulative incidence of relapse was significantly higher (43% vs. 29%, respectively, p = 0.006), while the cumulative incidence of non-relapse mortality (NRM) was significantly lower (9% vs. 23%, respectively, p < 0.001) in the PTCy-haplo group. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was lower in the PTCy-haplo group compared to the UCBT group (29% vs. 41%, respectively, p = 0.016), while those of grade III-IV acute GVHD and chronic GVHD were not statistically different between the two groups. Our results suggest that both PTCy-haplo and UCBT are viable alternatives to HLA-matched stem cell transplantation.

Immune reconstitution and survival of patients with parvovirus B19 related pure red cell aplasia after haplo-PBSCT.

Parvovirus B19 (PvB19) infection and PvB19 related pure red cell aplasia (PRCA) in recipients with allogeneic hematopoietic stem cell transplantation have been reported sporadically. However, clinical studies with large sample sizes are lacking, especially in patients undergoing HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). In addition, clinical features, immune reconstitution, and outcomes of these patients are not clear. We conducted a retrospective analysis of 164 patients who received haplo-PBSCT with low-dose anti-thymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide (PTCy)-based regimen as graft-versus-host disease (GVHD) prophylaxis. We analyzed the incidence of PvB19 related PRCA and compared the clinical characteristics, immune reconstitution, incidence of GVHD, relapse rate, and survival between patients with and without PvB19 related PRCA. A total of 14 (8.5%) recipients developed PvB19 related PRCA after a median of 5.3 months after haplo-PBSCT. These patients with PvB19 related PRCA had slower immune reconstitution, but similar incidences of GVHD, relapse rate, and overall survival compared with recipients without PvB19 related PRCA. PvB19 related PRCA indicated relative delayed and poor immune reconstitution of the recipients early after haplo-PBSCT. PvB19 related PRCA had no effects on GVHD, relapse, and survival.

Effectiveness of T-Cell Replete Haploidentical Hematopoietic Stem Cell Transplantation for Refractory/Relapsed B Cell Acute Lymphoblastic Leukemia in Children and Adolescents.

Background: The prognosis of refractory/relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains dismal owing to acquired resistance to chemotherapeutic agents. This study aimed to evaluate the efficacy of T-cell replete HLA haploidentical hematopoietic stem cell transplantation (TCR-haplo-HSCT) for pediatric refractory/relapsed BCP-ALL (RR-BCP-ALL).Methods: Nineteen pediatric patients with RR-BCP-ALL underwent TCR-haplo-HSCT between 2010 and 2019 at the Fukushima Medical University Hospital. The disease status at TCR-haplo-HSCT included complete remission (CR) in eight patients and non-CR with active disease in 11 patients. Total body irradiation-based, busulfan-based, and reduced-intensity conditioning regimens were employed in 11, 6, and 2 patients, respectively. Low-dose anti-thymocyte globulin (thymoglobulin, 2.5 mg/kg) was used in all patients. Graft-vs.-host disease (GVHD) prophylaxis was administered with tacrolimus, methotrexate, and prednisolone.Results: All patients received peripheral blood stem cells as the stem cell source. The HLA disparities in graft vs. host directions were 2/8 in one, 3/8 in five, and 4/8 in 13 patients. Among 18 patients who achieved primary engraftment, acute GVHD occurred in all 18 evaluable patients (grade II, 9; grade III, 8; grade IV, 1), and chronic GVHD was observed in 10 out of 15 evaluable patients. Three patients died because of transplant-related mortality. The 3-year overall survival (OS) and leukemia-free survival rates were 57.4 and 42.1%, respectively. Compared to patients older than 10 years in age (N = 10), those younger than 10 years in age (N = 9) showed an excellent OS rate (3-year OS rate: patients < 10 years old, 100%; patients > 10 years old, 20% [95% confidence interval, 3.1–47.5]; p = 0.002).Conclusions: We suggest that TCR haplo-HSCT with low-dose ATG conditioning has the potential to improve the transplantation outcomes in patients with RR-BCP.

The Comparision of Immune Reconstitution after HLA-Haploidentical Stem Cell Transplantation and HLA-Identical Sibling Stem Cell Transplantation

Title: The comparision of immune reconstitution after HLA-haploidentical Stem Cell Transplantation and HLA-identical sibling Stem Cell Transplantation.Background: HLA-haploidentical Stem Cell Transplantation is widely used in allogeneic hematopoietic stem cell transplantation in recent years. Previous studties reported that HLA-haploidentical Stem Cell Transplantation(HRD) has comparable GVHD and similar overall survival (OS) to HLA-identical sibling stem cell transplantation(MSD). While the immune reconstruction after transplantation was less studied and the effect of early and successful immunologic reconstitution on transplantation outcome still need further research.Methods: A total of 162 patients with hematologic malignancies who underwent allo-HSCT at Nanfang Hospital between January 2013 and December 2015 were enrolled in the retrospective study. Of the 162patients, 52 cases received HRD, 110 MSD. We sequentially monitored the reconstitution kinetics of CD3+T cells, total CD4+T cells, CD4+CD45RA+ T cells, CD4+CD45RO+ T cells, CD8+ T cells, CD8+CD45RA+ T cells, CD4+CD25+FOXP3+Treg cells, CD19+ B cells, CD3-CD56+ NK cells in all patients by flow cytometry.Results: Our results showed that in the first 30 days after grafting, counts of T cell subsets (total CD4+ T cells, CD45RA+CD4+ T cells, CD45RO+CD4+ T cells, total CD8+ T cells, CD45RA+CD8+ T cells,CD4+CD25+FOXP3+Treg cells) and CD3-CD56+ NK cell subsets were all signifcantly lower in haploidentical transplant recipients than those of HLA-matched transplant recipients, though no sigificant difference in the counts of B cells in two groups. The total CD8+ T cell numbers expanded dramatically and reach the level of that of HLA-identical recipients at day 90 post transplantation, though CD45RA+CD8+ T cells was still signifcantly lower in haploidentical transplant recipients than those of HLA-matched transplant recipients. Since day 180 post transplantation, CD8+ T cells were signifciantly higher than that of HLA-identical recipients.Conclusion: HLA-haploidentical Stem Cell Transplantation show superior CD8+ T cells and NK cells reconstitution than HLA-identical sibling Stem Cell Transplantation, which might be associated with a superior GVL effect compared to MSD for high-risk patients.similar immune reconstitution as HLA-identical sibling Stem Cell Transplantation. DisclosuresNo relevant conflicts of interest to declare.

HLA-Haploidentical Stem Cell Transplant with Pre-Transplant Immunosuppression for Patients with Sickle Cell Disease

Allogeneic stem cell transplantation (HCT) is curative in patients with severe sickle cell disease (SCD) but a significant number of patients lack a HLA-identical sibling or matched unrelated donor. Mismatched related (haploidentical) HCT with post-transplant cyclophosphamide(PTCY) allows expansion of the donor pool but is complicated by high rates of graft failure. In this report, we describe a favorable haploidentical HCT approach in a limited cohort of sickle cell patients with significant co-morbidities. To reduce the risk of graft failure we administered the conditioning regimen of rabbit anti-thymocyte globulin, busulfan (BU) and fludarabine (FLU) preceded with two courses of pre-transplant immunosuppressive therapy (PTIS) with FLU and dexamethasone (DEX). Graft-versus-host disease (GVHD) prophylaxis consisted of PTCY on days +3 and +4 followed by tacrolimus and mycophenolate mofetil (MMF) starting on day +5. Four patients (ages 13, 19, 19 and 23 years) received T-cell replete haploidentical stem cell infusion. All patients engrafted with 99.9-100% donor chimerism and all patients continue with stable engraftment at the last follow up (5 - 11 months post-transplant). Time to neutrophil engraftment was 14-26 days. Two patients had high levels of donor specific anti-HLA antibodies (DSA), which required the implementation of an antibody management protocol. This facilitated neutrophil engraftment on day +16 and day +26 respectively. One patient developed grade 1 acute GVHD which resolved. 3 patients developed mild, limited skin GVHD which responded to conventional immunosuppressive therapy. Human herpes virus 6 (HHV6) viremia was detected in three patients but resolved without treatment. One patient developed asymptomatic Cytomegalovirus (CMV) viremia which responded appropriately to standard therapy with ganciclovir. The prompt, stable engraftment and low toxicity in the post-transplant period makes PTIS with haploidentical transplant a promising option for the patients with SCD. DisclosuresSun:Baxalta: Consultancy. Wang:Magenta Therapeutics: Consultancy.

277 - Interim Analysis of a Pilot Study: Flu/Mel/TBI Peripheral Blood HLA-Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide and Bortezomib (Cy2Bor3)

277 - Interim Analysis of a Pilot Study: Flu/Mel/TBI Peripheral Blood HLA-Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide and Bortezomib (Cy2Bor3)

264 - Survival According to Conditioning Regimens in Patients Who Underwent HLA-Haploidentical Stem Cell Transplantation in a Single Center in Colombia

264 - Survival According to Conditioning Regimens in Patients Who Underwent HLA-Haploidentical Stem Cell Transplantation in a Single Center in Colombia

Cytokine release syndrome after HLA-haploidentical stem cell transplantation with posttransplant cyclophosphamide

Cytokine release syndrome after HLA-haploidentical stem cell transplantation with posttransplant cyclophosphamide

Immune reconstitution after T-cell replete HLA haploidenticalhematopoietic stem celltransplantation using high-dose post-transplant cyclophosphamide.

As HLA haploidentical related donors are quickly available, HLA haploidentical hematopoietic stem cell transplantation (haploHSCT) using high-dose post-transplant cyclophosphamide (PTCy) is now widely used. Recent basic and clinical studies revealed the details of immune reconstitution after T-cell replete haploHSCT using PTCy. T cells and NK cells in the graft proliferate abundantly at day 3 post-haploHSCT, and the PTCy eliminates these proliferating cells. After ablation of proliferating mature cells, donor-derived NK cell reconstitution occurs after the second week; however, recovering NK cells remain functionally impaired for at least several months after haploHSCT. PTCy depletes proliferating cells, resulting in the preferential accumulation of Treg and CD4+ T cells, especially the memory stem T cell (TSCM) phenotype. TSCM capable of both self-renewal and differentiation into effector T cells may play an important role in the first month of immune reconstitution. Subsequently, de novo T cells progressively recover but their levels remain well below those of donor CD4+ T cells at the first year after haploHSCT. The phenotype of recovering T cells after HSCT is predominantly effector memory, whereas B cells are predominantly phenotypically naive throughout the first year after haploHSCT. B cell recovery depends on de novo generation and they are not detected until week 4 after haploHSCT. At week 5, recovering B cells mostly exhibit an unconventional transitional cell phenotype and the cell subset undergoes maturation. Recent advances in immune reconstitution have improved our understanding of the relationship between haploHSCT with PTCy and the clinical outcome.

Survival in Patients Who Underwent HLA-Haploidentical Stem Cell Transplantation in Two Centers in Colombia

Introduction: Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for several malignant and non-malignant hematological diseases. However, sometimes it is challenging to find human leukocyte antigen (HLA)-matched related or unrelated donors, especially in minority populations such as Hispanics. Transplantation of T cell replete HLA haploidentical graft (HaploHCT) followed by a high dose post-transplantation cyclophosphamide (PTCy) to eradicate alloreactive T cells is an option for populations with low donor availability. HaploHCT has emerged as an effective and safe strategy in this population (Luznik L et al. BBMT 2008), but data in Hispanics is scarce. Objective: The aim of our study was to describe the clinical characteristics and assess overall survival at 100 days, 1- and 3-years of patients who underwent haploHCT in two Colombian reference centers. Methods: An observational retrospective study was conducted at two tertiary referral centers in Colombia. Patients who underwent haploHCT at Clinica FOSCAL and Centro Medico Imbanaco between January 2013 and January 2020 were selected. Demographic and clinical characteristics where analyzed using descriptive statistics. The Kaplan-Meier method was used to assess overall survival (OS) rates and the log-rank test was used to compare survival rates between groups. All data were analyzed using R statistical software®. Results: Seventy-six patients were included. Mean age at transplantation was 34 years (range 18-60). Forty-two (57.89%) patients were female. Average body mass index was 19.86kg/m2. The majority of patients (57%) had a pre-transplantation ECOG performance status of 2. The most common indication for haploHCT was acute lymphoblastic leukemia (55.26%), followed by acute myeloid leukemia (23.64%). A sibling was the donor in 69.74% of the cases. Forty-seven (61.84%) patients were ABO-matched group. Peripheral blood stem cells were the graft source in 96% of the patients. The average number of infused CD34+ cells was 11.15 x 106/kg. Fludarabine-melphalan was the most commonly used conditioning regimen (57%), followed by fludarabine-busulfan-thiotepa (39%). Graft-versus-host disease (GVHD) prophylaxis consisted of PTCy (50 mg/kg/day) on days 3 and 4 after HCT and a calcineurin inhibitor plus mycophenolate mofetil from day 5 to day 35 post-HCT. Median time to neutrophil engraftment (neutrophils &amp;gt; 0,5x109/L) was 15 days (range 10-33), while platelet engraftment, defined as as the second day of unsupported platelet count of ≥20 × 109, occurred at a median time of 13 days (range 5-38) post-transplantation. On day 28 post-HSCT, 93.4% of the patients had achieved 100% chimerism. OS was 91% (95%CI 84-97.5) at 100 days, 81% (95%CI 72-90) at 1-year, and 77% (95%CI 68-88) at 3-years after HaploHCT. C onclusion: The results of our haploHCT retrospective study in a Hispanic population are comparable to several other cohorts that have reported similar outcomes of haploHCT compared to HLA-matched HCT. The OS rates reported in our study suggest that haploHCT is a viable option in patients without an HLA-matched related or unrelated donor available, especially in populations with lower rates of suitable donors. Acknowledgements: We deeply thank Gonzalo Gutiérrez García, M.D. for his leadership and guidance implementing the haploHCT program in Clinica FOSCAL. Disclosures Peña: Roche: Honoraria. Salazar:Janssen: Honoraria; Novartis: Honoraria. Sandoval-Sus:MorphoSys US: Consultancy; Janssen: Consultancy; Massive Bio: Consultancy; Celgene: Speakers Bureau. Sossa:Novo: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Roche: Honoraria.

Nonmyeloablative Conditioning Regimen before T Cell Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Advanced Hodgkin and Non-Hodgkin Lymphomas.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a valid option in patients with refractory lymphomas. HLA haploidentical stem cell transplantation (haplo-SCT) expanded the accessibility to allogeneic hematopoietic cell transplantation. The aims of study were to retrospectively assess the toxicity and efficacy of haplo-SCT using nonmyeloablative conditioning in patients with advanced lymphoma. In total, 147 patients with advanced lymphoma at 2 partner institutions were included. Patients received a uniform nonmyeloablative conditioning regimen and graft-versus-host disease (GVHD) prophylaxis. The primary endpoints were progression-free survival (PFS), overall survival (OS), GVHD, nonrelapse mortality, and GVHD, relapse-free survival (GRFS). Median follow-up was 39 months (range, 6 to 114 months). The median age was 46 years (range, 19 to 71 years). Sixty-five percent of patients were in complete remission (CR) at transplantation. Cumulative incidence of grade II to IV acute GVHD was 30% (95% confidence interval [Cl], 23% to 38%). Two-year cumulative incidence of all grades of chronic GVHD was 13% (95% CI, 8% to 20%). Two-year cumulative incidence of disease relapse was 19% (95% CI, 14% to 27%), with a higher incidence in patients not being in CR at allo-HCT (CR versus not CR: 12% versus 33%, P = .006). Two-year PFS, OS, and GRFS were 66% (95% CI, 59-75), 73% (95% CI, 66-81), and 56% (95% CI, 48-65), respectively. Haplo-SCT with post-transplantation cyclophosphamide may be considered a valid option for patients with aggressive lymphoma and deserves further evaluation.

Haploidentical transplantation for hematologic malignancies: where do we stand?

The fundamental obstacle to the successful application of partially HLA-mismatched related donor, or HLA-haploidentical stem cell transplantation, is the strength of the host and donor T-cell response to allogeneic HLA molecules, which results in increased incidences of graft failure, GVHD, and nonrelapse mortality. The holy grail of haplo-SCT is to mitigate host-versus-graft and graft-versus-host responses while preserving immune responses to infection and the patient's malignancy. Two strategies have been taken to achieve this goal. The first strategy is to supplement a T cell-depleted graft with pathogen-specific T cells or populations of T cells in which alloreactivity can be controlled. The second strategy is to eliminate alloreactive T cells selectively from a T cell-replete graft. Substantial progress has been made with both approaches so that the safety of haplo-SCT now approaches that of SCT using grafts of umbilical cord blood or from HLA-matched donors. In light of the rapid and near universal availability of HLA-haploidentical related donors, it should now be possible to identify and mobilize a donor for every patient referred for allogeneic SCT. Prospective comparisons between haploidentical SCT and unrelated donor SCT should be performed to identify the most efficacious approach to alternative donor transplantation.