Allogenetic Hematopoietic Stem Cell Transplantation Research Articles

P779: OPTIMIZING TREATMENT OUTCOMES FOR CHILDREN WITH HIGHER-RISK MYELODYSPLASTIC SYNDROME UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Background: Myelodysplastic syndrome (MDS) are rare clonal hematopoietic disorders in children. Risk stratification system for adults is unfit for children. Refractory anemia with excess blasts(RAEB), acute myeloid leukemia with myelodysplasia-related changes(AML-MRC), monosomy 7 and complex karyotype always indicate poor prognosis. Hypomethylating agent (HMA) improved survivals of high-risk MDS in adults, and decitabine as part of conditioning regimen for allogenetic hematopoietic stem cell transplantation(allo-HSCT) was associated with favorable outcomes. However, these findings have not been tested in pediatric cohorts broadly. Aims: To evalute the efficacy and safety of hypomethylating agents as a part of pre-transplant treatments and contidioning regimens in children with higher-risk MDS. Methods: Patients from 1 to 14 years of age who were diagnosed with higher-risk MDS and underwent allo-HSCT consecutively between February 2019 and August 2020 in Pediatric Blood Diseases Center were enrolled. All identified patients were retrospectively reviewed with a collection of clinical data, laboratory test results, and outcome. Results: We reviewed 18 pediatric patients with higher-risk MDS, including 7 with RAEB, 8 with AML-MRC, and 3 with refractory cytopenia of childhood with monosomy 7. Regardless of initial diagnosis, monosomy 7 is the most common cytogenetic aberration (8/18, 44.4%). Next-generation sequencing (NGS) was performed on 15 specimens and the most frequent detection of mutation gene was SETBP1, followed by ETV6. Before transplantation, ten patients received monotherapies or combined chemotherapies with HMA, two patients received AML-like chemotherapies, and nine of those achieved bone marrow complete remission. The stem cell sources came from matched sibling donor (n=1), haploidentical donor (n=11), and unrelated cord blood (n=6), respectively. Low-dose decitabine-containing myeloablative conditioning regimens were administered in all cases. About 50% of patients (n=9) experienced Grade II- IV acute graft versus host diseases post-transplant. The cumulative incidence of transplantation-related mortality (TRM) was 11.1%. During a median follow-up of 10.5 (range, 2–36) months after transplantation, 15 of 18 patients were alive. At time of last follow-up, all survivors had resolution of hematologic disorder without relapse. Summary/Conclusion: In summary, administration of hypomethylating agents to allogeneic SCT resulted in excellent outcomes in children with higher-risk MDS.

Combination of Homoharringtonine with Venetoclax and Azacitidine Excerts Better Treatment Response in Relapsed /Refractory Acute Myeloid Leukemia

Overexpression of Bcl-2 is known to be an important factor for drug resistance in relapsed /refractory acute myeloid leukemia (R/R-AML). Combination of Bcl-2 inhibitor venetoclax with hypomethylating agents (HMA) has shown promising killing effect in elder patients with newly diagnosed AML, also worked in R/R-AML but with low rate of complete response (CR). High expression of Bcl-XL and/or Mcl-1 is the main reason for resistance to venetoclax. As an inhibitor of both Bcl-XL and Mcl-1, homoharringtonine (HHT) has presented a synegetic effect with venetoclax in inhibition of Mcl-1 and killing of lymphama. In this study, we analyzed the treatment response and safety of combination of HHT (1mg/m2 d1-7) with venetoclax (400mg d1-14) and azacitidine (75mg/m2 d1-7) (HVA) in R/R-AML. From 6, 2019 to 5, 2020, in Nanfang Hopsital, 22 patients with RR-AML were treated with HVA (HVA group), with a median age of 39(16-62) years, previous chemotherapy of 3(1-7) cycles. 15 (68.2%) relapsed within one year after allogenetic hematopoietic stem cell transplantation (allo-HSCT) and 12 (54.5%) previously exposed to HMA treatment. Meanwhile, 7 patients with RR-AML were treated with venetoclax combined with HMA (control group), with a median of 42(31-74) years, previous chemotherapy of 3(1-6) cycles. 2 (28.6%) relapsed after allo-HSCT and 5 (71.4%) had HMA exposure. In HVA group, totally 11/17(64.7%) patients acquired treatment response, and 7/15(46.7%) obtained CR/CRi, of whom 6 presented minimal residual disease (MRD) negative. While in control group, only 2/7(28.6%) acquired treatment response and 1 obtained CR. Subgroup analysis in HVA group showed allover response rate (ORR) was 9/13(69.2%) and CR rate was 6/11(54.5%) (all with MRD negative) in the patients with allo-HSCT. And in the patients without allo-HSCT ORR was 2/4(50.0%) and CR rate was 1/4. With a median follow-up of 6(1-7) months, one patient was bridged to allo-HSCT, 2 out of 7 patients with CR relapsed. All patients were well tolorated to both treatment regimens, showing as a median neutropenia of 9.5(5-14) days, 5 patients with Febrile neutropenia and 4 with pulmonary infection. In conclusion, combination of HHT with venetoclax and azacitidine (HVA) excerts better treatment response in R/R-AML, especially in those with allo-HSCT, and shows well tolorated. A multi-center prospective clinical trial (NCT04424147) has been initiated. Key words: HVA regimen, relapsed /refractory acute myeloid leukemia, treatment response, safety Disclosures No relevant conflicts of interest to declare.

PS1553 EFFICACY OF HAPLOIDENTICAL ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR 40 CASES WITH SEVERE APLASTIC ANEMIA

Background:Severe aplastic anemia is an acquired marrow failfure syndrome. Allogenetic hematopoietic stem cell transplantation is the main method to cure SAA. But the chance of finding a matched sibling donor of human leukocyte antigen is less than 30%. While looking for matched unrelated donor in the China hematopoietic stem cell donor database is in a longer period,with low probability and the donor is easy to regret, which may delay the transplantation time.At present, haploidentical hematopoietic stem cell transplantation with SAA has matured,the donor is readily available,parents and compatriots are with good compliance. And a number of studies have shown that Haplo‐HSCT treatment of SAA and MSD‐HSCT treatment of SAA is equivalent,overall survival is no significant difference.Aims:To investigate the efficacy and prognosis of Haplo‐HSCT for SAA.Methods:The clinical data of 40 SAA cases with Haplo‐HSCT from September 2013 to December 2017 were retrospectively analyzed. 33 SAA patients received peripheral blood hematopoietic stem cells,7 SAA patients combined with bone marrow hematopoietic stem cells. The conditioning regimen contained cyclophosphamide,fludarabine and antithymocyte globulin,with or without busulfan or low dose total body irradiation. Cyclosporin A,short term methylaminopterin and mycophenolate mofetil were used for preventing graft versus host disease(GVHD).Results:(1) Of 40 cases with Severe Aplastic Anemia which have undertook Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation,the median counts of mononuclear cell and CD34+ stem cell were 5.3(range,2.0–13.5) × 108/kg and 5.6(range,1.6–15.9) × 106/kg,respectively. (2) Implantation:Among 40 SAA cases,hematopoiesis reconstitution was achieved in 36 cases(90.0%). The median times for myeloid engraftment and platelet engraftment were 15(range,10–25) and 17(range,10–58)days,respectively. (3) Acute graft‐versus‐host disease:The incidence of acute graft‐versus‐host disease(aGVHD) was 40.0% (16/40), grades II‐IV aGVHD 22.5% (9/40), grades III‐IV aGVHD 15.0% (6/40). The incidence of Chronic GVHD(cGVHD) was 25.0% (10/40),extensive cGVHD 12.5% (5/40). (4) Clinical efficacy:26 (70.0%) SAA cases alived at median follow‐up time of 353 (30–1226) days,the cumulative overall survial(OS) was 67.8% ± 7.8,and the average time was 826 ± 85days. Within 100 days after stem cell infusion,transplantation‐related death(TRM) within 100 days was 12.5%. (5)Univariate analysis show the overall survival is significantly correlation with the disease classification, the count of CD34+ stem cell, with or without GVHD,with or without severe infection, with or without virus infection, with or without fungal infection (P<0.05). Multivariate logistis analysis show disease classification and severe infection is an independent risk factor affecting the overall survival of haploidentical hematopoietic stem cell transplantation in SAA.Summary/Conclusion:1.If the immunosuppressive therapy is not effective,and without matched sibling and unrelated donors for severe Aplastic Anemia,Haplo‐HSCT is a viable and effective method,which needs to be studied in a large number of cases for enhancing overall survial.2.In Haplo‐HSCT,it is important to reduce the risk of infection caused by various factors as far as possible. For the existing infection,timely anti‐infective treatment is necessary to delay its further development.

A Retrospective Analysis of Transplantation Related Mortality in 515 Cases of Children β-Thalassemia Major

Objective: At present allo-genetic hematopoietic stem cell transplantation (Allo-HSCT) remains the only consolidated curative approach for β- thalassemia major. How to reduce transplantation related mortality is the key to improve the curative ratio. Hence, the aim of this study was to retrospectively analyze the clinical data of 27 cases of β- thalassemia major in children who were died related allo-HSCT, and sum up the death factors related to transplantation as well as clinical experience.Methods: There were 515 children with β- thalassemia major who underwent transplantation in Nanfang Hospital from December 2008 to December 2017. In this study, we used the life tables and chi-square test in SPSS 20.0 statistical software to analyze the survival rate, causes of death and related factor.Results: In our center, the nine-year disease-free survival was 90%±3%, and the transplantation related mortality was 6%±1%. A total of 27 dead patients including 20 boys and 7 girls underwent 30 transplantations at the age from 7-month-old to 14-year-old, while median age was 5-year-old, with 20 human leukocytes antigen (HLA) matched donors and 10 HLA mismatched donors. As for source of stem cell, 23 transplantations used peripheral blood stem cell (PBSC), 1 transplantation used umbilical cord blood (CB), 2 transplantations used bone marrow (BM), 1 transplantation used PBSC+CB, 2 transplantations used BM+CB and 1 transplantation used PBSC+BM+CB. Before transplantation, the mean values of cardiac ejection fraction, serum ferritin and erythrocyte infusion were 69.3%, 3555.5ng/ml and 94.5 infusions, respectively. During transplantation, the mean mononuclear cells(MNC) and CD34+ cells were 7.7×10^8/kg and 5.1×10^5/kg respectively. Granulocytes were engrafted in +17.2 days and platelets were engrafted in +22.8 days. After HSCT, 25.9% of deaths occurred within 100 days and 81.5% within one year. Thirteen cases( 48.1% ) died of graft versus host disease (GVHD) or GVHD combined with infection. Eight cases( 29.6%) died of severe infection (including 1 case of severe dengue fever). Two cases died of hepatic vein obstruction disease(HVOD). Two cases died of bone marrow failure. One case died of hypoxic ischemic encephalopathy and one case died of hemolytic uremia syndrome. Compared with the incidence of GVHD and infection, GVHD had no significant correlation with infection (χ2= 3.095, P=0.128). At last, pulmonary infection was the most common complication (24/27, 88.9%).Conclusion: The mortality of transplantation in our center was 6%±1%. This study showed that the majority of deaths occurred within 1 year of transplantation. The most common causes of death were acute or chronic GVHD and infection. Pulmonary infection was the most common complication in the cases of death. However, there was no significant correlation between the incidence of GVHD and infection. Therefore, strategies of prophylaxis of GVHD and infection should be strengthened, and the dialectical relationship between the GVHD and infection still need to be further investigated. DisclosuresNo relevant conflicts of interest to declare.

The effect of Balance Exercise Assist Robot (BEAR) to patient after allogenetic hematopoietic stem cell transplantation (allo-HSCT): Preliminary study

Previous studies have shown that patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) frequently complicate balance dysfunction, with at least 50% experiencing one or more falls during hospitalization. We investigated the effect of Balance Exercise Assist Robot (BEAR) on patients after allo-HSCT, and the correlation between the effect of BEAR and the severity of balance dysfunction before intervention. Fifteen patients, who were allowed to leave the sterile room after allo-HSCT during hospitalization, participated. Mini-Balance Evaluation Systems Test (mini-BESTest), grip power, knee extension strength, 10-m walk test, Timed Up and Go test (TUG), dual-task TUG, functional reach test, Berg balance scale, sub-items of the mini-BESTest, and single-leg standing time were evaluated before and after intervention using BEAR. The participants performed 15 BEAR sessions, 20 minutes per session. The difficulty level of training task was automatically adjusted for each participants by BEAR. We divided into two groups based on pre-intervention Mini-BESTest scores: less than 70% (low group) and 70% or more (high group) and analyzed. Statistical analyses were performed to compare the groups; P < 0.05 indicated statistically significant differences. Informed consent was obtained from all participants before the intervention. There was no significant difference in pre- and post-intervention mini-BESTest in the low group (52.4 ± 15.9 vs. 70.8 ± 18.5) and high group (86.9 ± 12.0 vs. 88.5 ± 13.0). However, change between pre- and post-intervention scores in the low group was greater than the minimally important change of the mini-BESTest. Furthermore, significant improvement was observed between pre- and post-intervention scores for postural response (18.5 ± 22.7 vs. 51.9 ± 32.8), a mini-BESTest sub-item, in the low group. The other pre- and post-intervention outcomes were not significantly different in either group. BEAR was an effective and safe balance training, especially for postural response, in allo-HSCT patients with pre-intervention scores of less than 70% in the mini-BESTest.

Research Progress on Effect of JAK Inhibitors on Myelofibrosis- Review

Myelofibrosis(MF) is a type of myeloprolifirative neoplasms which is difficult to be treated. With the discovery of V617F mutation site in Janus kinase 2 (JAK2), JAK inhibitor provides a new treatment strategy for patients with myelofibrosis. Since 2011 the FDA in USA approved the first generation of JAK inhibitor Ruxolitinib for marketing, a growing number of JAK inhibitors have been entering into the clinical trials and showed a certain clinical efficacy. On the one hand, some JAK inhibitors for single application can effectively relieve the clinical symptoms of patients with myelofibrosis, slow down disease progression, and prolong the survival; on the other hand, JAK inhibitor can also be applied in combination with traditional or other new targeted drugs for MF patients, even during the allogenetic hematopoietic stem cell transplantation, thus providing more choices for targeted therapy on the patients with myelofibrosis. This review focuses mainly on the latest advances of JAK inhibitors for the patients with myelofibrosis.

Clinical features and prognosis of acute myeloid leukemia with acquired trisomy 21

To delineate the clinical features and prognostic significance of acquired trisomy 21 (+21) in 31 patients with acute myeloid leukemia (AML). Chromosome specimen was prepared from bone marrow samples using a direct method and (or) cultivation, and their karyotypes were analyzed with R banding. The clinical features, chemotherapeutic effect and survival status of patients with acquired +21 were evaluated. Cytogenetic studies were successfully performed on 3 329 patients with newly diagnosed AML, among which 31 (0.93%) had acquired +21. And 16 (0.48%) of the 31 patients had +21 as the sole abnormality. The most frequent subgroup of bone marrow morphology was AML-M5b, and its total number was 12 (38.7%) of the total. Thirty patients among those with +21 received standard chemotherapy. The complete remission (CR) rate (63% vs. 80%, P< 0.05) and median overall survival (OS) (7 months vs. 15 months, P< 0.01) of AML patients with acquired +21 were both lower than those without. Age (60 years or older) was associated with a significantly lower CR rate (30% vs. 80%, P< 0.05) and shorter median OS (4 months vs. 12 months, P< 0.01). Comparing to acquired +21 with other additional abnormalities, acquired +21 solely was associated with a lower median OS (6 months vs. 12 months, P< 0.05), but did not affect the CR rate (60% vs. 67%, P> 0.05). Three patients undergoing allogenetic hematopoietic stem cell transplantation (allo-HSCT) were still alive at the end of follow-up. Their survival time have reached 56, 36 and 105 months, respectively, which were remarkably longer than those only received chemotherapy (P< 0.01). The presence of acquired +21 in patients with AML has a adverse prognosis with or without other additional abnormalities. Older age (60 years or older) and +21 alone predicted relatively poorer outcome. Allo-HSCT was expected to prolong the survival time of AML patients with acquired +21.

Therapeutic effects of hydrogen on chronic graft‐versus‐host disease

The incidence of chronic graft‐versus‐host disease (cGVHD) is rising recent years, which has been the leading cause of non‐transplantation mortality post allogenetic hematopoietic stem cell transplantation (HSCT). Imbalance of inflammatory cytokines and fibrosis plays critical roles in the pathogenesis of cGVHD. Recent studies showed that molecular hydrogen has anti‐inflammatory, antioxidant, anti‐fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on cGVHD. To determine whether hydrogen could protect mice from cGVHD in an MHC‐incompatible murine bone marrow transplantation (BMT) model, survival rates of mice were calculated, and skin lesions were also evaluated after BMT. This article demonstrated that administration of hydrogen‐rich saline increased survival rate of cGVHD mice. Administration of hydrogen‐rich saline after transplantation also reduced skin lesions of cGVHD mice. Previously, we reported the therapeutic effects of hydrogen on acute GVHD. However, there was no report on the therapeutic effects of hydrogen on cGVHD mice. It is suggested that hydrogen has a potential as an effective and safe therapeutic agent on cGVHD. This study will provide new ideas on the treatment of cGVHD and has important theoretical values.

New progress in etiology of central nervous complications after allogeneic hematopoietic stem cell transplantation

With the progress of allogenetic hematopoietic stem cell transplantation (allo-HSCT), especially umbilical cord blood transplantation (UCBT), central nervous system(CNS) complications after transplantation have become more prominent. At present, the etiological analysis of such complications mainly focuses on infection, treatment-related toxicity, immune response, cerebrovascular events, infiltration of primary tumor and so on. In this article, we review the new progress in etiology of CNS complications after allo-HSCT. Key words: Hematopoieic stem cell transplantation; Cord blood stem cell transplantaion; Central nervous system; Complications

Bone Marrow Derived Mesenchymal Stromal Cells Reduce the Incidence of Chronic Graft-Versus-Host Disease after Allogenetic Hematopoietic Stem Cell Transplantation

Background Chronic graft-versus-host disease (cGVHD) is the common long-term complication and the leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which has a significant impact on patient quality of life. Currently, mesenchymal stromal cells (MSCs) have been considered as a promising therapy for treating refractory acute/chronic GVHD and engraftment failure (EF) or poor graft function (PGF), but the efficacy of MSCs in the prophylaxis of cGVHD is rarely reported. Methods Eighty-two patients who received MSCs treatment after allo-HSCT were enrolled in our study, including 45 patients with refractory aGVHD, 33 patients with EF or PGF and 4 patients with virus infection. In order to evaluate the influence of bone marrow (BM) derived MSCs for the incidence and severity of cGVHD, 308 consecutive patients who underwent allo-HSCT in the same period but without MSCs treatment were considered as the control group. And no statistical significance was found between the two groups for the demographic and transplant characteristics. MSCs were given at a median dose of 1×106 cells/kg once weekly. Results All eighty-two patients in MSC group received a median of 5 (range:3-12) doses of MSCs per patient. In MSC group, seventeen patients (20.7%) had cGVHD, including 14 patients with limited cGVHD and 3 patients with extensive cGVHD. In the control group, 140 patients (45.5%) had cGVHD, including 95 patients with limited and 45 extensive cGVHD. The 2-year cumulative incidence of cGVHD was 26.7% (95%CI: 16.1%-37.5%) in MSC group and 50.4% (95%CI: 37%-63.8%) in the control group (P=0.037). Furthermore, the extensive cGVHD (3/82) in the MSC group were also significantly lower than those (45/308) in the control group (P=0.021). In addition, at a median follow-up time of 189 (range: 112-1035) days post-transplantation, 4 patients relapsed in MSC group and 13 patients relapsed in the control group. The incidence of tumor relapse was not different between the two groups (P=0.629). No short-term toxic side effects were observed and other secondary tumor occurred after MSCs treatment. Conclusion MSCs derived from BM reduce the incidence and severity of cGVHD after allo-HSCT, but not increase the risk of tumour relapse. DisclosuresNo relevant conflicts of interest to declare.

Antifungal prophylaxis of patients undergoing allogenetic hematopoietic stem cell transplantation in China: a multicenter prospective observational study.

BackgroundAntifungal prophylaxis is currently regarded as the gold standard in situations with allo-genetic hematopoietic stem cell transplantation (allo-HSCT). However, the epidemiological information regarding prophylaxis of invasive fungal diseases (IFDs) is not clear in China.MethodsWe report the first large-scale (1053 patients) observational study of the prophylaxis and management of IFDs among patients with allo-HSCT in China.ResultsThe incidence rates of IFD after primary antifungal prophylaxis (PAP), secondary antifungal prophylaxis (SAP), and non-prophylaxis were 22.7 vs. 38.6 vs. 68.6 %, respectively (P = 0.0000). The median time from transplantation to IFD was 45 days in PAP patients, 18 days in SAP patients, and 12 days in non-prophylaxis patients. Aspergillus spp. represents the most common type of fungal infection. Independent risk factors for IFD in allo-HSCT patients with PAP were age, having human leukocyte antigen (HLA)-haploidentical or matched unrelated donor, decreased albumin levels, and the use of itraconazole as the prophylactic antifungal agent. Among SAP transplant recipients, there was no significant risk factor for IFDs. The incidence rates of overall survival (OS) in the PAP, SAP, and no prophylaxis groups were 85.07, 78.80, and 74.82, respectively (P = 0.01).ConclusionsThis observational study indicates that prophylaxis of IFD is helpful to reduce the incidence of IFDs and improve the OS of patients after allo-HSCT.

Circulating CD14(+) HLA-DR(-/low) myeloid-derived suppressor cells in leukemia patients with allogeneic hematopoietic stem cell transplantation: novel clinical potential strategiesfor the prevention and cellular therapy of graft-versus-host disease.

Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous cell population that includes immature myeloid cells and the progenitor cells of macrophages, dendritic cells (DCs), monocytes, and neutrophils. The expansion and functional importance of MDSCs in patients with cancer and noncancer pathogenic conditions has been recognized. As a result, there has been growing interest in understanding their roles in acute graft‐versus‐host disease (aGVHD) after allogenetic hematopoietic stem cell transplantation (allo‐HSCT). In order to evaluate possible effects of MDSCs on aGVHD development and clinical outcomes, this study systematically detected the dynamic changes of MDSCs accumulation in patients during the first 100 days after allo‐HSCT, and investigated the levels of other cell types and relative cytokines during MDSCs accumulation. Results showed that accumulation of MDSCs in the graft and in peripheral blood when engraftment might contribute to patients' overall immune suppression and result in the successful control of severe aGVHD and long‐term survival without influence on risk of recurrence after allo‐HSCT. But MDSCs levels in the graft had more favorable predictive abilities. Furthermore, MDSCs proportion significantly increased in patients developing aGVHD after allo‐HSCT. It might be caused by secondary inflammatory response, especially related to high concentrations of IL‐6 and TNF‐α. But this accumulation would not be able to counterbalance the aggravation of aGVHD and would not have influence on clinical outcomes and risk of relapse. Overall, MDSCs might be considered as potential new therapeutic option for aGVHD and achieve long‐term immunological tolerance and survival.

Clinic Outcome of FLAG Regimen treating Patients with Refractory and Relapse Acute Myeloid Leukemia

To evaluate the efficacy of FLAG regimen for treating patients with refractory/relaspse AML and their progonistic factors. The 38 patients with median age 40.5 (range 13-69) were treated with FLAG regimen from July 2006 to July 2013 in hospital. According to disease status, all the patiens were divided into 4 different groups: early relapse group (3 patients), late relapse group (12 patients), first induction failure group (16 patients) and second induction failure group (7 patients); meanwhile, based on risk status, all above-mentioned patients were stratified into better (8 patients), intermediate (26 patients) and poor (4 patients) groups, respectively. Twenty two cases achieved complete remission, 5 cases achieved partial remission among 38 patients. The complete remission (CR) rate was 57.9% and the overall response (OR) rate was 71.7%. The CR rate was higher in first induction failure group (12/16, 75%) than that in second induction failure group (3/7, 42.9%) and late relapse group (6/12, 50%). In better group and intermediate group, the CR rates (5/8, 62.5%; 16/26, 61.5%) were higher than that in poor group (1/4, 25%). The risk status was associated with the CR rate (P = 0.03) [OR = 25.9(95% CI 1.2-545.4)]. The intermediate risk was favorable factor to CR. Out of 22 patients with CR, 12 patients received allogenetic hematopoietic stem cell transplantation (allo-HSCT) and 10 patients received large dose of cytarabine or other regimens as consolidation treatments, 6 patients who accepted allo-HSCT are still alive. The overall survival (OS) was 25 months. The univariate analyses showed that the response to FLAG was accociated with OS [HR = 0.246, CR vs NR (95% CI 0.07-0.79) P = 0.03]. The 2-year cumulative survial rates in CR group and PR group were 62% and 48%, respectively. The 18- month cumulative survival rate was 73% in better group, 52% in intermediate group, 36% in poor group (P = 0.17); and 65% in first induction failure group and 32% in second induction failure group (P = 0.19). The efficacy of FLAG regimen has been confirmed to be effective for patients with refractory and relapse AML. The patients who achieved remission could acquire benefit from following HSCT or other consolidation chemotherapy, and their survials could be improved.

Mesenchymal Stem Cell As a Salvage Treatment for Patients with Refractory Bronchiolitis Obliterans Syndrome after Allogenetic Hematopoietic Stem Cell Transplantation

Background Bronchiolitis obliterans syndrome (BOS) is the most detrimental late pulmonary complications after allogeneic hematopoietic stem cell transplantation, as it is characterized by non-responsiveness to treatment, leading to high morbidity and mortality. Mesenchymal stem cell (MSC) has been considered as an effective treatment for refractory aGVHD, but the response to treat cGVHD, especially refractory BOS, is rarely reported. This study evaluated the efficacy of MSC from bone marrow (BM) of a third-party donor to BOS patients.Methods Fifty-three patients with refractory BOS were enrolled in our prospective study, including 29 patients in MSC group and 24 patients in non-MSC group. All patients had previously failed to at least 2 lines of immunosuppressive therapy. MSCs were given at a median dose of 1×106 cells/kg once weekly for 4 weeks as one cycle treatment. The responsiveness of MSC was evaluated after one cycle, non-responsive patients discontinued MSC treatments, others continued to accept another cycle of MSC treatments.Results Fifty-three patients developed BOS at a median time of 172 days (range, 94 to 398). After a total of 169 doses of MSC were administered, with a median of 6 (range:3-11) doses per patient, the overall response (OR) rate in MSC group was 75.9%, including CR in 13.8% and partial response (PR) in 62.1%. Compared with MSC group, OR rate in non-MSC group was 16.7%, including CR in 4.2% and PR in 12.5% (P=0.000; P=0.233; P=0.000, respectively). Furthermore, the efficacy of MSC to refractory BOS was significantly related with the severity of pulmonary function (mild VS severity, P=0.039). During the median follow-up time of 814 (range:228-2499) days post-transplantation, 7 patients were dead in MSC group, while 18 patients died in non-MSC group. The 5-year OS post-transplantation in MSC group were 68.6%±5.7%, compared with 21.2%±7.1% in non-MSC group (P=0.033). No patients experienced any toxic side effects and other secondary tumors after MSC treatment.Conclusion MSC derived from BM of third-party donors is a promising treatment for patients with refractory BOS. DisclosuresNo relevant conflicts of interest to declare.

Dynamic Change and Impact of Circulating Myeloid-Derived Suppressor Cells in Patients Following Allogeneic Hematopoietic Stem Cell Transplantation

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population involved in tumor-associated immunosuppression and played immune regulatory roles in malignancies, infectious disease, autoimmune disease, trauma and inflammatory disease. Based on the significant suppressive functions, MDSCs raises great interests in the field of allogenetic hematopoietic stem cell transplantation (allo-HSCT) and graft-versus-host disease (GVHD). In recent years, studies described the immunosuppressive functions of CD14+HLA-DR-/low MDSCs, one of the few well-characterized MDSC subsets in human. However, the studies in patients with allo-HSCT are still scanty. This study identified the phenotype of CD14+HLA-DR-/low MDSCs and systematically monitored the dynamic changes of MDSCs accumulation in patients during the first 100 days after allo-HSCT in order to evaluate possible effects of MDSCs on aGVHD development and clinical outcomes. We also detected the frequencies of other cell types and concentrations of relative cytokines during MDSCs accumulation. Results showed that accumulation of MDSCs in the graft and in peripheral blood when engraftment might contribute to patients' overall immune suppression and result in the successful control of severe aGVHD and long-term survival without influence on risk of recurrence after allo-HSCT. However, the level of MDSCs in the graft had more favorable predictive abilities compared with that in PBMCs when engraftment. Furthermore, MDSCs frequencies were significantly increased in patients developing aGVHD after allo-HSCT.In the patients with mild aGVHD (0-2), MDSCs accumulated at the time of engraftment after allo-HSCT and decreased to basal levels at about 4 weeks. MDSCs frequencies would keep in stable levels with slight fluctuations in the following weeks. But, in patients with severe aGVHD (3-4), MDSCs elevated slightly when engraftment. When aGVHD occurred, MDSCs frequencies would significantly increase. And a synchronized reduction of the levels of MDSCs was observed after effective management of aGVHD with immunosuppressive therapy. Besides, the levels of IL-10, IL-6, TNF-α, Arg-1, iNOS and HO-1 increased greatly both in patients with aGVHD and in high MDSCs group. It is speculated that MDSC accumulation at the onset of aGVHD might be caused by secondary inflammatory response, especially related to high concentrations of IL-6 and TNF-α. But the accumulation would not be able to counterbalance the aggravation of aGVHD and would not have influence on clinical outcomes and risk of relapse in future. Overall, we suggested that MDSCs might be considered as a potential new approaches to regulate transplant rejection and achieve the recipient host long-term acceptance and survival. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Progress of Clinical Trials on Bone Marrow Mesenchymal Stem Cells for Prevention and Therapy of Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is a major complication following allogenetic hematopoietic stem cell transplantation, which shows a great threat to patients' survival and life quality. Along with multiple differentiation potential to various types of progenitor cells, bone marrow mesenchymal stem cells (BMMSC) have been confirmed to possess low immunogenicity and exert favorable immunomodulation. The recent studies show that the safety and high efficiency of BMMSC to prevent and cure GVHD greatly improved survival rate of the hosts. The most recent progress on prevention and therapy of GVHD is summarized in this review based on biology of BMMSC and pathogenesis of GVHD, so as to provide the effective evidence for further research.

Nutritional status and its related factors in patients undergoing allogenetic hematopoietic stem cell transplantation

Objective We tried to investigate the nutritional status and related factors in patients undergoing allogenetic hematopoietic stem cell transplantation. Methods A total of 75 patients were re-cruited from a class-three hospital in Suzhou. They were investigated with a basic information questionnaire and the Patient-Generated-Subjective Global Assessment (PG-SGA). The related factors influencing nutri-tional status were analyzed. Results The PAB level began to rise since conditioning regimen, and it rose to the highest level in the second week, then began to decline. The weight and the BMI had been declining in the four weeks since conditioning regimen. 29.33% of the patients were malnourished, the scored PG-SGA was (5.60±4.96), the percentage of patients with dietary problems was 33.3% before conditioning regi-men; 85.33% of the patients were malnourished, the scored PG-SGA was (19.26±7.18), the percentage of patients with dietary problems was 93.2% in the second week since conditioning regimen; 85.33% of the patients were malnourished, the scored PG-SGA was (12.95±6.19), the percentage of patients with dietary problems was 75.8% in the fourth week; Age is the main factor affecting the patients' albumin level in the second week. Conclusions The nutritional status of patients deteriorated and the percentage of patients with malnutrition increased during allogeneic hematopoietic stem cell transplantation. Clinical staff should pay atten-tion to the assessment of nutritional status, and give a reasonable nutritional support when necessary. Key words: Allogeneic hematopoietic stem cell transplantation; Nutritional status; Nutritional as-sessment

The Use of Imatinib with Chemotherapy and Allogeneic Hematopoietic Stem Cell Transplantation Improves Survival of Philadelphia Positive Acute Lymphoblastic Leukemia in Adults

Philadelphia positive acute lymphoblastic leukemia (Ph + ALL) accounts for approximately 20% -30% of all adult ALL. The prognosis of patients with Phi + ALL is unfavorable when treated with standard chemotherapy schemes, presenting a long-term survival of 15% -20%. Since the introduction of Imatinib (IM) to treatment regimens the survival of these patients has improved, although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option. We conducted a retrospective analysis of Ph + ALL patients before and after IM became available in order to analyze the impact of IM on survival in adult Phi + ALL.Patients and methodsBetween April 1997 and April 2013 we diagnosed 120 over 15 year old patients with ALL (B and T lineage), 31 (25.8%) of which were Phi +, all B lineage. Of these 31 cases, 30 were treated with protocols from Spanish group PETHEMA with curative intent. 14 of them (47%) were treated with chemotherapy and Imatinib (IM cohort) and 16 (53%) with chemotherapy (pre-IM cohort). In 17 of the 30 cases allogeneic HSCT was performed, 7 in the pre-IM cohort and 10 in the IM cohort. In the post-transplant period, two patients were treated with Dasatinib due to positive minimal residual disease (BCR-ABL1 positive). The probabilities of overall survival (OS) (death) and event free survival (EFS) (no response, relapse or death) were estimated using the Kaplan-Meier product limit method. Differences between groups were tested using the X2 test. Univariate analysis was performed using Cox regression models or log-rank test. Multivariate analysis was performed using Cox proportional hazards regression model. The study was conducted in accordance with the Declaration of Helsinki.ResultsThe median age was 38 years (range, 15-66 years), 17 patients were males and 13 females. The whole series survival was 32.4 ± 9.2%. The OS mean of the pre-IM cohort was 3.1 years (CI 95%, 0.5-5.7) and 6.9 years (CI 95%, 4.4-9.4) in the IM cohort (figure 1). The main characteristics of both groups are reflected in Table 1.When we analyzed the EFS, the variables that influenced it were being treated with IM (48% in the IM cohort versus 12.5% in the pre-IM cohort, p = 0.03), having received an allogeneic HSCT (45% versus 8%, p = 0.004) and being in first complete remission before allogeneic HSCT (51% versus 0%, p <0.001).In the analysis of OS, the only variables with prognostic significance were: treatment with IM (63% in the IM cohort versus 12.5% in the pre-IM cohort, p = 0.01) and having received an allogeneic HSCT (55 % versus 0%, p <0.001). When the 17 patients that received allogeneic HSCT were analyzed separately, OS in the pre-IM cohort was 29 ± 17% versus 79 ± 13% in the IM cohort (p = 0.057).Table 1Patient characteristics (N=30)CharacteristicPre-IM cohort(N=16)IM cohort(N=14)PFemale/Male7/96/80.96Age ² 40 years12 (75%)10 (71%)0.82³ 50 x109/L WBC8 (50%)4 (29%)0.23Transcript type: e1a2 b2a2/b3a212 (75%) 4 (25%)11 (79%) 3 (21)0.83Morphological CR after induction13/15 (88%)13/13 (100%)0.17No. of Allo-HSCT7 (44%)10 (71%)0.13CR pre Allo-HSCT: 1CR 2CR5 (71%) 2 (29%)10 (100%) 0 (0%)0.07Relapse8/13 (61.5%)4/13 (31%)0.12Exitus14 (87.5%)5 (36%)0.003Abbreviations: IM, imatinib. WBC, white blood cells. CR, complete remision. Allo-HSCT, allogenetic hematopoietic stem cell transplantation. [Display omitted] ConclusionsIn our study we show how adult Phi + ALL patients who are treated with chemotherapy associated with IM and subsequently receive an allogeneic HSCT exhibit a higher overall survival rate than those treated in the pre-IM era. Although Phi + ALL is still considered of very high risk, in our series of patients treated in the IM era, with a follow-up of over 7 years, overall survival was of 63%, higher than that of historical series of adults with Phi negative ALL.This work has been financed by a grant from the Malaga Association for Research in Leukemia "AMPILE" and the FIS 11-01966 project. DisclosuresNo relevant conflicts of interest to declare.

Clinical Study of Allogenetic Hematopoietic Stem Cell Transplantation for Three Cases of Leukodystrophy

AbstractAbstract 4559 Objective:Allogenetic hematopoietic stem cell transplantation (Allo-HSCT) can be used to cure some genetic leukodystrophy patients in current. This clinical study is to investigate efficacy and practicability of Allo-HSCT in treatment of genetic leukodystrophy in China. Methods:Three boy diagnosed genetic leukodystrophy (2 cases of metachromatic leukodystrophy, 1 case of X□|linked adrenoleukodystrophy) had undergone allogeneic Stem cell Transplantation. A 32 month old boy accepted HLA 8/10 high-resolution matched unrelated umbilical cord blood as graft, which contained nucleated cells 13.5×107/kg. A 2 year-old boy accepted HLA high-resolution 10/10 matched unrelated peripheral blood stem cells (PBSC) as graft which contained mononuclear cells 8 ×108/kg. The conditioning regimen consisted of cyclophosphamide (60–100 mg/kg), fludarabine (150–200mg/kg), TT (5mg/kg) and busulfan (12–13.2 mg/kg). A 12 year-old boy accepted sibling HLA low resolution 6/6 (A, B, DRB1) matched bone marrow as graft which contained mononuclear cells 1.23 ×108/kg. The conditioning regimen consisted of busulfan (16mg/kg) and cyclophosphamide (200mg/kg). Cyclosporine A and mycophenolate mofetil were used to prevent graft versus host disease (GVHD). ATG-Fresenius (15 mg/kg) and low dose of methotrexate were added for prophylaxis of GVHD in unrelated PBSC transplantation. XY chromosome by the FISH method or quantitative PCR for short tandem repeat (STR) were used to identify the chimerism. ASA level in peripheral blood leukocytes and C26:0 plasma level were monitored after transplantation respectively. Results:1.Complete chimerism and hematopoietic reconstitution were successfully achieved in 3 patients, the ANC engrafted from +10 to +17 days, the time of platelets>20×109/L was from +11 to +35 days.2.Arylsufatase A level in peripheral blood leukocytes was significantly increased to the normal range in 2 cases of metachromatic leukodystrophy on day +28 and were stable in monthly detection for 4–5 months. C26:0 plasma level began to decrease on the 2nd months after transplantation, and reached to normal range on the 8thmonth after transplantion in the case of X□|linked adrenoleukodystrophy.3.The 3 patients have survived for 4,5 and 50 months respectively up to now. One patient with severe CNS symptoms before transplantation got recurrent lung infection after transplantation related to the swallowing difficulty. Another 2 patients have no progressive disease.4.Three patients have not got any acute graft-versus-host-disease. Conclusion:Allogenetic hematopoetic stem cell transplantation is effective and feasible in the treatment of some childhood genetic leukodystrophy patients. These patients should accept allo-HSCT in the early stage of disease in order to get good survival. Disclosures:No relevant conflicts of interest to declare.

Hepatic Sinusoidal Obstruction Syndrome After Allogenetic Hematopoietic Stem Cell Transplantation in Adult Acquired Aplastic Anemia

Abstract 3012▪FN2▪This icon denotes a clinically relevant abstractThe hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease [VOD]) is an acute complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the actual incidence and outcomes after alloHSCT in patients with adult acquired aplastic anemia (AA) was not defined yet. We investigated the incidence, risk factors and outcomes of SOS in AA. Data was taken from our previous retrospective study comparing matched sibling donors versus alternative donors (KSBMT07-02 study) and prospective randomized phase III study comparing cyclophosphamide (Cy)-ATG and Cy-fludarabine (Flu)-ATG (COSAH C-004A study) in patients with adult acquired AA.Total 260 patients were included in this analysis. SOS developed in 7.3% (n=19/260). SOS patients were male in 13 (68.4%), related donors in 84.2%, HLA full-matched in 73.7%, same donor-recipient sex matching in 63.2% patients. There were no TBI containing conditioning regimen and all patients received Cy containing conditioning regimen. The majority (94.7%) received ATG as condition regimen; horse ATG in 73.7% and rabbit ATG in 21.1% patients. Classical Cy (200mg/m2)-ATG was the most common conditioning regimen (84.2%). Sixteen patients (84.2%) received preventive medication of SOS and the major drug was heparin (78.9%). Among the diagnostic criteria of SOS, weight gain was observed in 17 (89.5%); hepatomegaly in 14 (73.7%); hyperbilirubinemia in 17 (89.5%) patients. The average total bilirubin was 6.65 (range 1.8–26.9) mg/dL. The severity of SOS was mild in 10 (52.6%), moderate in 6 (31.6%) and severe in 3 (15.8%) patients. Treatment for SOS were supportive care (72.2%), UDCA (16.7%) and corticosteroid (11.1%). All severe cases died of SOS and one moderate case died of multiple organ failure combined with infection without recovery of SOS. Therefore the mortality of SOS was 4/19 (21.1%). The probability of mortality by SOS had no correlation with weight gain (p=1.000), hepatomegaly (p=0.524), hyperbilirubinemia (p=1.000), maximal total bilirubin (p=0.239) or maximal direct bilirubin value (p=0.184). The frequencies of SOS were not significant in male (p=0.126), older than 31y (p=9.8%), prior IST (n=10/116, 8.6%; p=0.465), prior ATG usage for IST (p=0.846), unrelated donor (p=0.216), HLA mismatch (p=0.340), female to male matching (n=3/46, 6.5%; p=0.935), ABO incompatible (n=10/125, 8.0%; p=0.680), TBI conditioning (p=0.232), cyclophosphamide (p=1.000), ATG conditioning (p=0.325), fludarabine condition (p=0.221), busulfan conditioning (p=1.000), cyclosporine prophylaxis for GvHD (p=0.272), methotrexate prophylaxis for GvHD (p=0.170), bone marrow as a stem cell source (p=1.000). However, Cy 200mg/m2 conditioning (p=0.035), classical Cy-ATG condition (p=0.007) and horse ATG conditioning (p<0.001) were significant risk factors in developing SOS in univariate analysis. Multivariate analysis revealed that only horse ATG conditioning was the poor prognostic factors (HR=3.484; 95% CI 1.226–9.904; p=0.002).In conclusion, SOS is a relatively rate acute complication of alloHSCT in AA (7.3%). However the mortality of SOS is still high under supportive care. Horse ATG conditioning regimen was a significant risk factor for developing SOS. Disclosures:No relevant conflicts of interest to declare.