HLA-identical Sibling Transplants Research Articles

Allogeneic Hematopoietic Cell Transplantation in Advanced Phase Mycosis Fungoides and Sézary Syndrome: A Retrospective Analysis of 57 Consecutive Patients

Background: Advanced stage Mycosis Fungoides (MF) and Sézary Syndrome (SS) are cutaneous T-cell lymphomas (CTCL) associated to dismal prognosis, with 5-year survival rates ranging from 47% for stage IIB to 18% for stage IVA2-IVB and with a high tendency to relapse. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered the only curative treatment option. Recently, allo-HCT from haploidentical donor (Haplo-HCT) has been increasingly used also in MF/SS patients. We hereby report an update on long-term outcome of MF/SS patients who underwent allo-HCT at our Center from 2001 to 2022, currently including a larger population with an increased proportion of Haplo-HCT. Methods: We retrospectively collected clinical data of all consecutive patients with MF/SS transplanted at our Center between September 2001 and May 2022. Conditioning was based on reduced intensity (RIC) regimens, including flaudarabine/cyclophosphamide/TBI200, pentostatin/TBI200, and fludarabine/melphalan in transplants from HLA-identical sibling and unrelated donor (UD), and the thiotepa/fludarabine/cyclophosphamide/TBI200 regimen in Haplo setting. GvHD prophylaxis consisted of CsA, MMF and ATG. Post-transplant cyclophosphamide was added in Haplo-HCT. Results: As of August 2022, 57 CTCL patients underwent allo-HCT at our Institution: 22 (38.5%) from a HLA-identical sibling, 13 (23%) from a 10/10 matched UD, 12 (21%) from a 9/10 or 8/10 matched UD, 1 (1.8%) from cord blood, and 9 (15.7%) from a Haplo donor. Median age at transplant was 55 years (range 20-67). Indication for allo-HCT was MF in 36 patients (63%) and SS in 21 patients (37%). Median number of previous treatment lines was 6 (range 2-11) with a median time from diagnosis to transplantation of 46 months (10-274). Disease status at transplant was complete remission (CR) in 14 cases (24.5%), partial remission (PR) in 35 (61.5%) and progressive disease (PD) in 8 (14%). Stem cell source was peripheral blood in 53 patients (92.9%), bone marrow in 3 (5.2%) and cord blood in 1 (1.8%). After a median follow up of 81 months, 30 patients (52%) were alive, of whom 23 (76%) in CR. Acute GvHD occurred in 29 patients (51%; grade III-IV in 13, 23%), while chronic GvHD in 19 (33%; moderate/severe in 10 patients, 17%). Cause of death was disease progression in 17 patients (62.5%), acute GvHD in 4 (15%), infection in 2 (7.5%) and other in 4 (15%). In the whole cohort, 5-yr overall survival (OS) and disease-free survival (DFS) were respectively 57.6% (95% CI 44-71) and 37.9% (95% CI 25-51). According to donor type, 5-yr OS was 69%, 39% and 89% and DFS 57%, 19% and 57% for HLA-identical sibling, UD and Haplo, respectively (Figure 1). 5-yr OS was significantly higher in SS versus MF patients (78% vs 47%, p=0.03) and in patients who were in CR at the time of transplant (100% vs 43.5%, p<0.001). In the Haplo setting,.disease status at transplant was CR in 1 pt and PR in 8. After a median follow-up of 26 months, 7 out of 9 patients (78%) were still alive and in CR. Acute GvHD occurred in 6 patients (66%), grade III-IV in 2 (22%), while chronic GvHD occurred in 3 patients (33%), moderate/severe in 1 (11%). Two patients relapsed at +5 and +2 months, of whom the latter died 157 days after HCT. Conclusions: After a median follow up of more than 9 years for alive patients, we confirm that RIC allo-HSCT is a powerful therapeutic strategy in selected patients with advanced CTCL, and particularly in SS. With the limitation of a shorter follow-up, transplant outcomes following allo-HCT from haploidentical donor appear to be associated with very low toxicity, excellent OS and DFS comparable to HLA-identical sibling transplants. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Similar Probabilities of Failure to Reach Transplantation and Transplant Outcomes after HLA-Identical Sibling or Unrelated Donor Transplant in Patients with Acute Myeloid Leukemia: A Single Institution Evaluation of a Donor Selection Algorithm

IntroductionThe increasing use of alternative donors has expanded allogeneic hematopoietic stem cell transplantation (HSCT) eligibility in patients with acute myeloid leukemia (AML) without HLA-identical siblings (matched-SIB). However, optimal donor selection remains controversial and current practice is largely based on transplantation centres' experience. Unrelated donor (URD) HSCT is associated with longer waiting times to transplantation than umbilical cord blood or haploidentical HSCT, but the impact of HSCT delays on transplantation rates and survival outcomes is unclear in this setting. In this study we evaluated the performance of a donor selection algorithm consisting in the allocation of patients with AML without matched-SIB to fully matched (8/8) or mismatched (7/8) URD.MethodsRetrospective analysis including adult patients with AML who received approval for first-time allogeneic HSCT with myeloablative conditioning at our institution between January 2011 and February 2017. Matched-SIB was the preferred donor choice for all patients. Fully matched (8/8) or mismatched (7/8) URD were selected through high-resolution HLA-A, HLA-B, HLA-C and DRB1 typing for those patients without an available matched-SIB. Non-parametric cumulative incidence and Kaplan-Meier estimates were obtained to assess transplantation and overall survival (OS) rates, respectively. Fine-Gray competing risks regression was used to identify predictors of failure to reach transplantation. Age, intention-to-treat (ITT) and disease status at the time of transplantation approval were included in the multivariate analysis.ResultsTable 1 summarizes the characteristics of the 113 eligible patients during the study period. Fifty-seven patients (50.4%) were allocated to a matched-SIB donor, whereas URD search was started in the remaining 56 patients (49.6%) without an available matched-SIB. Thirty patients (26.5%) failed to reach transplant after the approval to undergo transplantation. Figure 1 shows the cumulative incidence functions of transplantation from time of approval (Gray's p = 0.06). The estimated probabilities to reach transplantation were 74% and 71% for patients with or without a matched-SIB donor. Median time to HSCT from transplantation approval was shorter in patients with a matched-SIB donor (100 versus 136 days). Disease status at the time of transplantation approval was the only predictor of failure to reach transplantation in the multivariate analysis (sHR for any disease status versus CR1 = 1.69, p = 0.04). The 3-year OS from time of transplantation approval in the ITT population was 35% (28% versus 41% for patients with or without a matched-SIB donor, respectively; log rank p = 0.39), while the 3-year OS from time of transplantation was 46% (46% versus 54% for patients who underwent a matched-SIB HSCT or an URD HSCT, respectively; log rank p = 0.46).Conclusions8/8 or 7/8 URD selection in patients with AML without an available matched-SIB led to increased times to transplantation but did not have an impact on the probability of failure to reach transplantation and did not result in inferior survival outcomes in comparison with patients with a matched-SIB. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prophylaxis with ATLG Significantly Improves Chronic Graft-Versus-Host Disease / Relapse-Free Survival and Quality of Life after a Myeloablative HLA Identical Sibling Transplant for Acute Leukemia Patients in Complete Remission. Long-Term Follow-up of the Randomized ATG Familystudy

IntroductionChronic GVHD is a major complication after allogeneic stem cell transplantation (HSCT) affecting both survival and quality of life (QoL). Several strategies are currently used to limit the incidence and severity of GVHD. All but one prospective randomized studies demonstrated in the unrelated and related settings a significant reduction of cGVHD when anti-T cell lymphocyte globulin (ATLG) or anti-thymocyte globulin (ATG) is added to the standard GVHD prophylaxis (cyclosporine and methotrexate) with significant improvement of survival free from relapse and cGVHD (cGRFS), similar overall survival and no increase of relapse risk. In the setting of sibling transplants, the ATGfamilystudy demonstrated that in acute leukemia patients in complete remission the addition of ATLG (Grafalon, NEOVII) at the dose of 10 mg/kg per day from day -3 to day -1 to the standard GVHD prophylaxis within a myeloablative conditioning regimen resulted in a significant reduction of cGVHD (68.7% vs 32.2% at two years), especially of the extensive form (52.4% vs 7.6%) without a significant increase of relapse, infection and non relapse mortality (NRM). Overall survival resulted similar in the two arms while cGRFS was significantly improved (37% vs 16.7%). The risk of relapse is claimed as the major concern for a broader adoption of ATLG in the GVHD prophylaxis and a longer follow-up is strongly claimed by the scientific community to definitely unravel the issue of disease recurrence after in vivo T cell depletion with ATLG.MethodsWe updated the follow-up of the trial NCT 00612875 (Kröger et al. NEJM 2016) and analyzed data of QoL. The primary endpoint was the CI of cGVHD. CI of cGVHD, NRM, relapse, overall survival, disease-free survival and chronic GVHD and relapse-free survival (cGRFS) were analysed. The trial included also quality of life (QoL) questionnaires (EORTC QLQ-30 and HDC29 ) before and after SCT. The QLQ-C30 includes a global QoL scale, 5 functional scales (physical, role, emotional, cognitive and social function) and 9 symptom scales (fatigue, nausea-vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial problems).ResultsOut of 155 patients analyzed for safety and efficacy in the randomized study 119 were still alive at study end after 2 years and 114 provided any follow-up data. The median observation time was 5.2 and 6.0 years, in the experimental and control arm, respectively, with a maximum follow-up time >10 years in both groups.The CI of cGVHD overall was 31.3% (95% CI: 22.6% - 43.3%) in the ATLG arm vs 69.1% (95% CI: 59.1% - 80.7%) in the control arm (p <0.001); the CI of relapse was 36.6% (95% CI: 27.5% - 48.7%) and 23.9% (95% CI: 15.8% - 36.2%, p = 0.09). 5-ys overall survival, disease-free survival and cGRFS in the experimental and control arm were 61.8% and 67.1% (p=0.564), 53.6% and 61.7% (p=0.364), 40.4% and 18.1% (p = 0.001), respectively.Patients who received ATLG showed significantly greater improvement of global health status / QoL over time compared to non-ATLG (p=0.02), with a difference between the two arms of 2.8 ± 3.9 points (marginal mean ± SEM) at day 100 and increasing to 10.5 ± 5.3 points at month 24 in favour of ATG. Patients in the ATG arm showed also a significant superiority in 4 of the 5 functional scales as well as for several symptom scales scores such as appetite loss, insomnia, nausea-vomiting and dyspnea. For the QLQ-HDC29, significant treatment effects favoring ATG were observed for side-effects on gastrointestinal effects and impact on family, impact of family, urinary frequency, helping to distinguish what is important in life.ConclusionsThis long-term follow-up of the ATGfamilystudy confirmed a significant benefit of ATLG in reducing chronic GVHD without significant increase of relapse in patients with acute leukemia undergoing HLA-identical sibling allogeneic peripheral stem cell transplantation resulting in a significant benefit in chronic GVHD/relapse-free survival with a significant improved quality of life. DisclosuresBonifazi:Neovii: Honoraria. Solano:Neovii: Honoraria. Bethge:Neovii GmbH: Honoraria, Research Funding; Miltenyi Biotech GmbH: Consultancy, Honoraria, Research Funding. Kroeger:Neovii: Honoraria, Research Funding.

Allogeneic Blood and Marrow Transplantation for Pediatric Patients with Sickle Cell Anemia: An Institutional Experience

Introduction: Sickle cell anemia (SCA) is a genetic disease with potentially debilitating complications and shortened life-expectancy. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only cure for SCA, but is limited by the lack of available histocompatible sibling donors and transplant related morbidities. Alternative donor HSCT for SCA has been associated with variable outcomes. Methods: We conducted a retrospective review of all patients with SCA who underwent HSCT at our center between January 2014 and June 2017. Results: Table 1 shows the pre-HSCT characteristics of the study population (n=19). Candidates for HSCT were selected based on institutional and/or study eligibility criteria and were consented per the Declaration of Helsinki. The majority of patients were receiving chronic transfusions or hydroxyurea therapy. Two patients had concurrent autoimmune diseases and 79% had low 25-hydroxycholecalciferol levels (median 17.8 ng/ml). 9 patients (47.3%) received HLA-identical sibling transplants (MSD), 6 (31.5%) UD, and 4 (21%) α/β T cell depleted related haplo-identical (haplo) transplants. The median pre-HSCT comorbidity index (CI) was above 3 for patients receiving alternative donor transplants (>3 is associated with higher pre-HSCT acuity). HSCT characteristics are shown in Table 2. The majority of patients (68.4%) received bone marrow (BM), while 21% received mobilized peripheral blood stem cell (PBSC) grafts. All patients achieved initial high-level (>90%) donor chimerism. The median time to neutrophil engraftment (>500 cells/µL) was 14 days with significantly earlier engraftment seen among haplo recipients (median 10 days) compared to other graft sources (p < 0.02). The median time to platelet engraftment (>50,000 /µL) was 20 days. The median time to CD3+ T lymphocyte recovery (>200 cells/uL) was 195 days (range 20-384) (significantly earlier for the haplo group (figure 1a, p=0.01) and for CD19 (>66 cells/uL) was 104 (range 90-526) days post-HSCT (figure 1b). Secondary early graft rejection occurred in 2 patients who received haplo-identical HSCT, with sustained donor engraftment following a second transplant with the same donors in one of these patients. Overall incidence of > grade II (severe) acute graft versus host disease (GVHD) was 26%, with no significant difference observed among haplo recipients despite the absence of primary GVHD prophylaxis. Two UD recipients developed chronic GVHD (10.5% overall incidence). 11 (57%) patients (6 MSD, 3 UD, 2 haplo) developed CMV viremia, with one late onset disseminated CMV meningitis; 7 patients (36.8%) (3 MSD, 4 UD) developed adenoviremia; one patient developed HHV-6 viremia around the time of graft rejection. Both patients with concurrent autoimmune diseases did not experience significant post-HSCT complications. One patient with type I diabetes mellitus diagnosed 60 days prior to HSCT has had stable glycemic control. One patient with systemic lupus erythematous (SLE) remains in SLE remission post-HSCT. With a median follow-up of 568 (105-919) days, the overall 2-year survival was 84.2%. 88.8% for MSD, 83.3% for UD, and 75% (3 patients) survival for α/β T cell depleted haploidentical related HSCT (p=0.7) and a mean performance score of 90 among survivors. No adverse events were noted among donors with sickle cell trait, including 4 parent donors who received PBSC mobilization with either filgrastim and/or plerixafor. Conclusion: Alternative donor allogeneic HSCT should be considered for carefully selected patients with SCA. α/β T cell depleted related haplo-identical HSCT appears promising with low rates of severe acute GVHD in the absence of primary prophylaxis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Survival With Bone Marrow Transplantation Versus Hydroxyurea or Interferon for Chronic Myelogenous Leukemia

AbstractHydroxyurea, interferon, and HLA-identical sibling bone marrow transplantation are common therapies for chronic myelogenous leukemia (CML) in chronic phase. Which is best is controversial. The purpose of this study was to compare survival of patients with CML receiving HLA-identical sibling transplants versus hydroxyurea or interferon. The transplant cohort included 548 recipients of HLA-identical sibling transplants, reported to the International Bone Marrow Transplant Registry. The nontransplant cohort included 196 patients receiving hydroxyurea (n = 121) or interferon (n = 75) on a randomized trial of the German CML Study Group. Survivals were compared using proportional hazards regression with fixed and time-dependent variables to adjust for patient differences and changing risks over time. For the first 18 months after diagnosis, mortality was higher in the transplant than the nontransplant cohort (relative risk [RR], 5.85; P < .0001). From 18 to 56 months, mortality was similar (RR, 0.80; P = .38). After 56 months, mortality was lower in the transplant cohort (RR, 0.16; P < .0001). Seven-year survival probabilities (95% confidence interval) were 58% (50% to 66%) with transplant and 32% (22% to 41%) with hydroxyurea or interferon. There was a significant survival advantage for hydroxyurea or interferon in the first 4 years after diagnosis and for transplants starting 5.5 years after diagnosis. For transplants done within 1 year of diagnosis, the survival advantage for transplantation began earlier. Survival advantage for transplants was greater and occurred earlier in patients with intermediate- and high-risk prognostic features than in those with low-risk features. This study confirms higher early mortality, but a long-term survival advantage for HLA-identical sibling transplants over hydroxyurea or interferon in CML.

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

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

Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia

AbstractAllogeneic hematopoietic stem cell transplantation is the only curative therapy for myelodysplasia (MDS). To identify factors influencing transplantation outcome, we studied 452 recipients of HLA-identical sibling transplants for MDS from 1989 to 1997, reported to the International Bone Marrow Transplant Registry. Patients with treatment-related MDS or unclassified MDS were excluded. Median age was 38 years (range, 2-64 years). Sixty percent had refractory anemia with excess blasts (n = 136) or with excess blasts in transformation (n = 136). Conditioning regimens included total body irradiation in 199 (44%) cases. Marrow was T-cell depleted for 58 (13%) transplants. Cumulative incidences of neutrophil engraftment, grades II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were 91% (95% confidence interval [CI], 88%-93%), 36% (95% CI, 31%-40%), and 39% (95% CI, 33%-44%), respectively. Three-year transplantation-related mortality (TRM), relapse, disease-free survival, and overall survival rates were 37% (95% CI, 32%-42%), 23% (95% CI, 19%-27%), 40% (95% CI, 36%-45%), and 42% (95% CI, 37%-47%), respectively. Multivariate analyses showed that young age and platelet counts higher than 100 × 109/L at transplantation were associated with lower TRM and higher disease-free and overall survival rates. Relapse incidence was higher in patients with high percentages of blasts in the marrow at transplantation or presentation, with high International Prognostic Scoring System scores at diagnosis, and with T-cell–depleted transplants. These findings indicate that transplantation from an HLA-identical sibling offers the possibility of long-term, disease-free survival to patients with MDS. Best candidates are younger patients with a low percentage of blasts and preserved platelet counts.

A Prospective Comparison of Un-Manipulated Haploidentical (with PTCY) vs HLA-Identical Sibling Transplants for Different Hematologic Disorders: A Single Center Experience of 82 Patients in a Developing Country

A Prospective Comparison of Un-Manipulated Haploidentical (with PTCY) vs HLA-Identical Sibling Transplants for Different Hematologic Disorders: A Single Center Experience of 82 Patients in a Developing Country

G-CSF-Mobilized Blood and Bone Marrow Grafts as the Source of Stem Cells for HLA-Identical Sibling Transplantation in Patients with Thalassemia Major.

As an inherited anemia, thalassemia major (TM) is currently only curable with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here we report an allo-HSCT protocol for patients with TM who received a combination of granulocyte colony-stimulating factor-primed bone marrow and peripheral blood stem cells (G-BM & PBSCs) from a matched sibling donor (MSD). The conditioning regimen consisted of i.v. busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin. Chimerism analysis was performed for all patients. Immunosuppressive treatment was terminated if rejection was suspected, and donor lymphocyte infusion was administered once no response was observed. A total of 184 patients with TM were enrolled in the study between July 2007 and July 2018. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 13.1%, and that of moderate or severe chronic GVHD was 5.7%. The cumulative incidence of graft rejection was .6%. In the total cohort, the 3-year overall survival, thalassemia-free survival, and GVHD-free, relapse-free survival were 97.8%, 97.3%, and 89.5%, respectively. Collectively, our results indicate that G-BM & PBSCs from an MSD is be a good stem cell source for patients with TM undergoing allo-HSCT.

High Body Mass Index (BMI) Is Associated with Lower Survival and Increased Chronic GVHD after Allogeneic Hematopoietic Stem Cell Transplantation.

Introduction Contrary to conventional wisdom, the obesity epidemic is not restricted to industrialized societies. over 115 million people suffer from obesity-related problems in developing countries.(1) The traditional view of adipose tissue as a passive storage depot of excess energy has been challenged. Adipose tissue is a highly active endocrine organ with the capacity to synthesize and secrete a variety of adipokines creating a chronic inflammatory state. (2) We tested whether pre-transplant BMI can affect transplant outcomes in a homogeneous population of patients underwent HLA-identical sibling transplant with PBSCT graft. Objectives To investigate the impact of Pre-transplant BMI on HSCT outcome. Methods Adult patients who underwent Allo HSCT (2000-2014) at Nasser Institute for Research and Treatment, Cairo, Egypt, were included. Patients received their 1st allo HSCT from 6/6 HLA-matched sibling donors using PBSC graft for treatment of SAA, MDS, AML, ALL or CML. Patients aged >50 years and those who received syngeneic transplant were excluded. The final data set included 971 patients. Patients were classified according to pre-transplant BMI into five groups following WHO 2007 BMI classification system: underweight BMI HSCT outcome was assessed with the following parameters: time to engraft, development of acute GVHD, development of chronic extensive GVHD, relapse, non-relapse mortality and overall survival. Each outcome was adjusted for other statistically significant variables. Cox regression models were used to evaluate the impact of BMI on overall mortality, NRM, relapse, and cGVHD. Logistic regression was used to evaluate the relationship between BMI and AGVHD. Results Our results showed that obesity class II and III was associated with increased risk of developing chronic extensive GVHD (HR=1.98, 95% CI 1.12-3.53, P value 0.02), lower OS (HR=1.51, 95% CI 1.04-2.20, p=0.03) and higher non-relapse mortality rates (HR=1.55, 95% CI 1.04-2.30, p=0.03) compared to the average BMI group. Interestingly, overweight and obese class I but not Obese class II and III patients showed statistically significant earlier engraftment in the form of documented increase of absolute neutrophilic count (ANC) to 500/µL (P value 0.01 and Conclusions BMI ≥35 is a risk factor for increased mortality after allogenic HSCT after accounting for impacts of comorbidities. Pre-transplant weight reduction to a goal of BMI There is a rationale to consider T cell depletion for patients with pre-transplant BMI ≥ 35.

Impact of Graft Composition on Graft-Versus-Host Disease in Peripheral Blood HLA-Identical Sibling Transplants: Protective Role of CD8 Cell Dose

Introduction and Objective:Acute graft-versus-host disease (aGVHD) is a leading cause of transplant related mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Data on the impact of graft composition, namely CD34 and T-cell subsets, and aGVHD is conflicting. We hypothesized an upper cell dose limit of CD34 would exist predictive of aGVHD without affecting engraftment and sought to explore T-cell subsets and their impact on aGVHD outcomes amongst peripheral blood progenitor cell (PBPC) HLA-identical sibling transplants (Allo-Sib).Methods:In an IRB approved protocol, consecutive Allo-Sib patients underwent HSCT for hematologic malignancy at our center from 1/2004 to 12/2012. Demographic and clinical data were prospectively collected and retrospectively confirmed. Patients received the entire D1 CD34 PBPC collection from their donors and from a second day of collection if necessary to achieve a dose of 4 x 106 CD34/kg cells. aGVHD prophylaxis was uniformly tacrolimus and mini-methotrexate. Tacrolimus was monitored to achieve a trough of 10-15 ng/ml. aGVHD was graded as per the International Bone Marrow Transplant Registry System. Exact binary logistic regression models were used to estimate the odds of aGVHD as a function of patient demographic and clinical data. For the association between cell counts and aGVHD, binary cut scores were determined by finding the point along the receiver operating characteristic curve that maximized sensitivity and specificity. Non-parametric Spearman correlation coefficients were used to estimate the association between CD34, CD3, CD4, and CD8 cell counts.Results:We analyzed 160 consecutive patients. In this mostly male (63%) population, median age was 51 and most patients underwent a myeloablative transplant (93%). Disease risk as per Armand et al 2012 was low 45%, intermediate 13.2%, and high 41.7%. Co-Morbidity Index by Sorror et al (HCT-CI) was 30.5% for 0, 33.8% for 1-2, and 35.8% for > 2. Sixteen patients (10%) developed grade II-IV aGVHD while 9 (6%) developed grade III-IV aGVHD. Median CD34 cell dose infused was 6.27 X 106/kg. Median CD3, CD4, and CD8 cell doses infused were 2.51 X 108/kg, 1.80 X 108/kg, and 0.66 X 108/kg, respectively. In univariate analysis, patients (n=67) receiving > 9.94 x 106 CD34/kg were 12 times more likely to develop grade III-IV aGVHD (odds ratio =12.308; p=0.01)(figure 1). Conversely, patients receiving > 0.50 x 108 CD8/kg were less likely to develop grade II-IV aGVHD (odds ratio = 0.30; p=0.049)(Figure 2), but not Grade III-IV aGVHD. The only other factor associated with aGVHD was a diagnosis of AML, which was protective (p=0.01). CD3 and CD4 cell counts did not correlate with aGVHD in our patient cohort. There was no correlation between engraftment and CD34, CD3, CD4, or CD8 cell dose. Finally, we found no direct correlation between CD34 cells counts and CD3, CD4, or CD8 cell counts.Conclusion:This study represents the largest evaluation examining the correlation between both infused CD34 cells and T-cell composition with aGVHD among patients undergoing strictly matched related donor HSCT. Importantly, the data demonstrates patients receiving > 10 x 106 CD34/kg have increased risk of developing clinically significant aGVHD, a dose that far exceeds adequate engraftment doses and serves now as a cap on CD34 cell dose in our program. Interestingly, our data suggests infusion of > 0.50 x 108 CD8/kg may protect from severe aGVHD whereas prior reports have demonstrated no association between CD8 cells and aGVHD. Further investigation is needed to better characterize the relationship between CD8 cells and aGVHD and better define the correlation between CD8 and CD34 cell doses in the development of aGVHD. DisclosuresNo relevant conflicts of interest to declare.

Low-Dose Anti-T Lymphoglobulin as Prophylaxis for Graft-versus-Host Disease in Unrelated Donor Transplantations for Acute Leukemias and Myelodysplastic Syndromes

Chronic graft-versus-host disease (cGVHD) is a major complication after stem cell transplantation (HSCT). Several randomized studies already demonstrated that anti-T lymphoglobulin (ATLG) is effective in preventing GVHD after myeloablative unrelated and HLA-identical sibling transplants. However, the issue of doses and the potential increase of relapses still remain unsolved. Here we report data on 190 patients with acute leukemia and myelodysplastic syndrome who underwent an unrelated HSCT with low-dose ATLG (15 to 30 mg/kg) given at an earlier timing (days –6 to –2). HSCT was performed from HLA 10/10 (n = 62, 33%), 9/10 (n = 91, 48%), 8/10 (n = 30, 16%), and <8/10 (n = 7, 4%) identical unrelated donor. Peripheral blood was the stem cell source in 42% (n = 80). Median follow-up was 51 months. Grades II to IV and III to IV acute GVHD were 26% and 9%, respectively, and 2-year overall and moderate to severe cGVHD were 23% and 14%, respectively. The 3-year incidences of relapse and nonrelapse mortality were 26% and 18%, respectively. The rates of 3-year overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 60%, 56% and 44%, respectively. Factors such as younger donor, good performance status, and early disease were associated with better outcome in terms of OS, DFS, and GRFS. Our data indicate that doses of ATLG lower that those used in randomized clinical trials can be used for GVHD prevention, even in the adult setting, without clear increases in relapse and infections; these findings need to be further validated by a prospective randomized study.

Busulfan Fludarabine (BU-FLU) Compared to Thiotepa Busulfan Fludarabine (TBF) for Allogeneic Transplants in Acute Myeloid Leukemia (AML) or Refractory Anemia with Excess Blasts (RAEB) in Remission

▪INTRODUCTION The combination of Busulfan and fludarabine (BU-FLU) is considered a standard conditioning regimen for patients with acute myeloid leukemia undergoing an allogeneic hemopoietic stem cell transplant (HSCT) , especially in patient older than 40 years of age. However, in a recent prospective study, designed for patients in first or second remission (CR1 or CR2) the incidence of leukemia relapse at 3 years was 38%, both for patients receiving BU-FLU as well as for patients randomized to BU-CY (Lancet Oncol 2015;16:1525). The addition of thiotepa to a BU-FLU regimen (referred to as TBF) has shown promising control of leukemia, and has emerged as a standard regimen in cord blood (CB) transplants (BMT 2012; 47: 1287). The question is whether this holds true also for transplants other than CB grafts.Aim of the study : to compare Bu-FLU with TBF in patients with AML or RAEB, grafted in remission from related or unrelated donors.Methods: Eligible for this study were patients allografted between January 2008 and April 2017 with AML or RAEB in hematologic remission . Seventy-eight patients received the BU-FLU regimen (busulfan 3.2 mg/kg/day x4; and fludarabine 40 mg/m^2/day x4), and 127 received TBF(thiotepa 5mg/kgx2, busulfan 3.2 mg/kg/dayx3, fludarabine 50 mg/m^2x3). Graft-versus-host disease (GVHD) prophylaxis was as follows: in HLA identical sibling transplants , cyclosporin (CyA) and Metothrexate (MTX); in unrelated donor transplants CyA+MTX+ antithymocyte globulin (ATG) and for family haploidentical donors (HAPLO) , CyA, mycophenolate mofetil (MMF) and cyclofosphamide 50mg/kg given on day +3 and +5, after transplantation (PT-CY) . Supportive care and infectious disease prophylaxis, or pre-emptive therapy, were provided as per Institutional protocols. Clinical characteristics are shown in Table 1.Results: With a median follow up of 481 and 551 days (range, 8-2625 and 2-2277 respectively) after transplantation, the 5-year cumulative incidence of TRM was 25% and 9% for BU-FLU and TBF (p = 0.007); the 5-year cumulative incidence of leukemia relapse related deaths (RRD) was 33% and 9% (P = 0.008). TBF showed an advantage over BU-FLU, also after exclusion of HAPLO, both in TRM (p=0.08) and RRD (p=0.04). The 5-year actuarial survival was 41% (26-56%) and 82% (74- 90%) (p=0.000) respectively for the BUFLU and the TBF group. The survival advantage was seen also when looking only at HLA identical siblings and UD, excluding HAPLO grafts (51% vs 82%,p=0.05).In a multivariate Cox analysis, after correcting for patients age, interval diagnosis transplant, first or second remission , and donor type, the use of TBF reduced the risk of death as compared to BU-FLU (RR 0.3 , range 0.10-0.89, p=0.01) . This was true also when running a Cox model on TRM (RR 0.17 for TBF vs BU-FLU, p=0.02) . TRM was 4% vs 14% in patients receiving TBF vs Bu-FLU aged < 50 years (p=0.09), and 9% vs 32% in patients receiving TBF aged > 50 years (p=0.01). In a Cox analysis on RRD, TBF showed a reduced risk (RR 0.41) but this did not reach statistical significance (p=0.1)Conclusions: Superior survival of patients receiving TBF , as compared to BU-FLU appears to be a combination of reduced toxicity and reduced relapse. The survival advantage is independent of donor type, and therefore of GvHD prophylaxis. [Display omitted] DisclosuresLaurenti:Roche: Other: Advisory Board; Gilead: Other: Advisory Board; Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board. Angelucci:Celgene: Honoraria, Other: Advisory: research project ; Novartis Oncology Swiss: Other: Invited speakers sponsored satellite meeting during ; Novartis Oncology: Other: Advisory board: iron toxicity; Jazz: Other: Advisory board: AML; Roche: Other: Advisory board: biosimilars; Bluebird Bio: Other: Advisory board: Gene therapy in Thalassemia; Celgene: Other: protocoll ACE 536 B-Thal 001: DMC Chair; Novartis Oncology: Other: Protocol Telesto: sterring committee Chair.

Myeloablative Versus Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia in Patients with Prior Myelodysplastic Syndrome/ Myeloproliferative Disorders: An ALWP of EBMT Study

▪Secondary acute myeloid leukemia (sAML) includes a heterogeneous group of diseases evolved from myelodysplasia, myeloproliferative disorders (MDS/ MPN), bone marrow failure syndrome or after exposure to leukemogenic agents such as chemotherapy and/or radiation therapy for malignant hematological (other malignant hematological diseases) or solid tumors.Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy but relapse is a frequent cause of failure after HCT occurring in more than 50% of patients. No systematic large analysis of HCT for sAML has evaluated risk factors and outcome based on a prior diagnosis of MDS or MPN. Therefore, the EBMT Acute Leukemia Working Party (ALWP) performed a multicenter retrospective registry study on patients undergoing HCT for sAML following MDS/MPN comparing myeloablative (MAC) to reduced intensity conditioning (RIC). ALWP-EBMT supplemental data forms were used to establish the occurrence of any prior hematological disorder or non-hematological malignancy as well as details of cytogenetic data and therapy.We studied 811 patients with a previous diagnosis of MDS/ MPD and available cytogenetic data who had received HCT for sAML from an HLA-identical sibling (MRD, n=344 [42.4%]) or unrelated donor transplant (URD- 9/10 or 10/10) during 2000-16. Median time from diagnosis (sAML) to transplant was 137 days (IQR 94-204). Median age at HCT was 59.57 years (IQR 52-65). sAML with adverse cytogenetics accounted for 269 (33.2%) patients. At the time of HCT, 401 (49.5%) patients were in CR1 and 367 (45.3%) had active disease. Median follow-up of surviving patients was 32 months (IQR, 11-62).Regimen intensity was assessed by EBMT criteria. MAC regimens were used in 326 (40.2%) patients while 485 (59.8%) received RIC. Older patients were more likely to receive RIC than MAC regimens (p<0.001). Most patients received peripheral blood stem cell grafts (n=731 [90.3%]; MAC 85.6% vs RIC 93.4%, p<0.001). A total of 534 (67.9%) patients were cytomegalovirus (CMV) seropositive pre-HCT. There were no significant differences in disease characteristics (e.g. disease status at transplant, cytogenetic risk category), donor source, year of transplant or CMV serology status between MAC and RIC cohorts. All patients received a calcineurin inhibitor-based combination as prophylaxis against graft versus host disease (GVHD) and 516 (63%) received in vivo T-cell depletion (rATG 474 (58%).A total of 667 (95.2%) patients engrafted (MAC 94.5% vs. RIC 95.6%; p=0.596). Acute GVHD (grade II-IV) within 100 days of HCT occurred in 24% (95% CI, 21-27; MAC vs. RIC, p=0.126) and 2-year cumulative incidence of chronic GVHD was 33% (95% CI 30-37; MAC vs. RIC, p=0.150). Three-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 41% (95% CI, 38-45; MAC 37% [31-42] vs. RIC 45% [40-49], p=0.029) and 25% (95% CI, 22-28%, MAC 25% [20-30] vs. RIC 25% [21-29], p=0.959), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia free survival (LFS) at 3 years were 40% (95% CI, 37-44; MAC 44% [38-50] vs. RIC 38% [33-43], p=0.041) and 34% (95% CI, 31-38; MAC 38% [33-45] vs. RIC 31% [27-36], p=0.032), respectively (Figure 1).In multivariate analysis by Cox Regression, a higher RI was seen after RIC regimens (HR 1.72 [1.16-2.55]; p=0.0063). Patients receiving RIC regimens had a higher risk of chronic GVHD (HR 1.37 [1.02-1.84], p=0.0389). Non-relapse mortality (NRM) was equivalent in MAC and RIC groups.MAC regimens were associated with superior OS (HR 1.46, 95% CI 1.1-1.94; p=0.0085) and LFS (HR 1.37, 95% CI 1.02-1.85; p=0.0387). High risk cytogenetics and older age contributed significantly to inferior outcomes.In summary, this EBMT registry study of HCT for sAML after MDS/MPN is the largest cohort reported. Myeloablative conditioning regimens were associated with a lower relapse risk and superior survival. Given that NRM after HCT has declined in the current era, these data indicate that the outcome of HCT for sAML may be improved by careful patient selection for MAC regimens. Survival may be further enhanced by effective pre-HCT disease control (also associated with decreased NRM) and post-HCT pre-emptive therapy to decrease RI. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau. Ciceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Schmid:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; MoilMed: Membership on an entity's Board of Directors or advisory committees. Mohty:Sanofi: Honoraria, Speakers Bureau.

Superior GVHD-free, relapse-free survival for G-BM to G-PBSC grafts is associated with higher MDSCs content in allografting for patients with acute leukemia

BackgroundGranulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (G-PBSC) has largely replaced unstimulated bone marrow (un-BM) for allografting because of accelerated engraftment, but with a higher morbidity and mortality of graft-versus-host-disease (GVHD). Recent studies suggested that G-CSF-primed BM (G-BM) had similar engraftment but lower morbidity and mortality of GVHD comparing to G-PBSC. A prospective, randomized, multicenter study was conducted to compare G-BM with G-PBSC as the grafts in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemia in first complete remission (CR1).MethodsTotally 101 adult leukemia in CR1 undergoing HLA-identical sibling transplants were randomized into G-BM or G-PBSC group. The primary study endpoint was GVHD-free/relapse-free survival (GRFS).ResultsBoth the engraftment of neutrophil and platelet were 2 days later in G-BM than in G-PBSC group (P = 0.412, P = 0.39). G-BM group showed significantly lower II–IV acute GVHD (aGVHD) and similar III–IV aGVHD compared with G-PBSC group (12.2% vs 28.8% for II–IV, P = 0.048; 4.1% vs 9.6% for III–IV aGVHD, P = 0.267, respectively). The overall cumulative incidence of chronic GVHD (cGVHD) at 3 years were 22.3% ± 6.3% and 44.8% ± 7.6% (P = 0.026), respectively, and extensive cGHVD were 4.5% ± 3.1% and 15% ± 5.3% (P = 0.08), respectively, in G-BM and G-PBSC groups. Two groups had similar 3-year relapse, transplant-related mortality (TRM), overall survival (OS), and disease-free survival (DFS) (all P > 0.05). G-BM group showed significantly higher probability of GRFS than G-PBSC group (73.5% ± 6.3% vs 55.8% ± 6.9% at 1 year, P = 0.049; 69.0% ± 6.7% vs 49.7% ± 7.0% at 2 and 3 years, P = 0.03, respectively). Graft content analysis revealed statistically higher frequency of myeloid-derived suppressor cells (MDSCs) in the G-BM than in G-PBSC grafts (P < 0.01), and recipients received statistically higher numbers of MDSCs in G-BM than in G-PBSC group (P = 0.045). Numbers of MDSCs infused to patients were negatively correlated with the severity of aGVHD (P = 0.032, r = −0.214). Multivariate analysis showed that MDSC cell dose below the median (HR = 3.49, P < 0.001), recipient age (HR = 2.02, P = 0.039), and high risk of disease (HR = 2.14, P = 0.018) were independent risk factors for GRFS.ConclusionsG-BM grafts lead a better GRFS and less GVHD associated with a higher MDSCs content compared with G-PBSC grafts.

Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation

AbstractDespite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.

HLA-Haploidentical Donors Seem to be Not Inferior to HLA-Identical Sibling Donors for Hematopoietic Stem Cell Transplantation of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Background PNH is an acquired clonal disorder of the hemopoietic stem cells for which the only curative treatment is allogeneic hematopietic stem cell transplantation (allo-HSCT). But allo-HSCT is challenging for those who have no HLA-matched donors.Several recent studies have shown that haploidentical HSCT for patients with hematological malignancy can achieved comparable outcomes with HLA-identical sibling transplantation . There are very few reports on the use of haploidentical HSCT for PNH . Is haploidentical HSCT a valid alternative option for patients with PNH?Methods 19 PNH patients received allo-HSCT between Dec 2007 and Oct 2015 at our institution. 12 donors were HLA-haploidentical and 7 were HLA-matched siblings. The patients were aged 8 to 54 years (median 28 years) . Of the 12 haploidentical donors, 6 were siblings, 2 fathers,2 mothers,1 son and 1 daughter. 12 patients with haploidentical donors received a myeloablative conditioning regimen consisting of busulfan, cyclophosphamide and ATG (anti-thymocyte globulin), 7 patients with identical siblings were given a reduced intensity conditioning. G-CSF-mobilized bone marrow and peripheral blood stem cells were transplanted as graft. Prophylaxis for graft-versus-host disease (GVHD) consisting of cyclosporine or tacrolimus + short-term methotrexate + mycophenolate mofetil was used for 12 patients with haploidentical donors, and cyclosporine + short-term methotrexate for 7 with identical siblings.Results All 19 patients were engrafted successfully. The median time of neutrophils (ANC) reached to 0.5×109/L and platelets (PLT) reached to 20×109/L was 12 days and 15 days in haploidentical group , and that to identical group was 11 days and 13 days ,respectively. There were 2 patients developed grade II acute GVHD in haploidentical group while 1 patients with grade IV aGVHD in identical group . Limited chronic GVHD was observed in 2/12 patients in haploidentical group and 1/7 patients in identical group. After a median follow-up time of 22.0 (range 4.0-42.0) months, the 3-year OS probability was 77.8±13.9% and 85.7±13.2% for haploidentical and identical group,respectively (P=0.03). 2 patients died of treatment-related mortality in haploidentical group, including severe pulmonary infection (n=1) and transplant-associated thrombotic microangiopathy (n=1) ,and 1 died of severe aGVHD in identical group. No patients were documented to have a recurrence of a PNH clone after HSCT in both groups.Conclusion This report seemed that long-term outcomes of HLA- haploidentical HSCT in patients with PNH were comparable to that of HLA- matched donor at our institution . Haploidentical HSCT should be considered as a valid alternative option for PNH patients without HLA- matched donors . DisclosuresNo relevant conflicts of interest to declare.

Low Incidence of Chronic Gvhd after Haploidentical T-Cell Replete Peripheral Blood Stem Cell Transplantation with Post Transplantation Cyclophosphamide (PT-Cy)

Background:Since the first publication at the John Hopkins Hospital, (Luznik et al. BBMT 2008), Haploidentical T-cell replete Stem Cell Transplantation (HaploSCT) with post transplantation cyclophosphamide (PT-Cy) has become a reproducible and feasibility therapeutic option for many patients (pts) with hematologic malignancies , notably because of the low incidence of GVHD and infections, without increased graft failure. Initially, bone marrow (BM) was considered as the favorite source of hematopoietic stem cells in order to minimize the risk of GVHD. In a retrospective study, we previously showed no difference in terms of increased events (GVHD, NRM), regardless of the hematopoietic stem cell source (PBSC or BM) (Castagna et al. BMT 2014). Some recent publication seems to confirm this observation (Sugita J. BBMT 2015 , Solomon R. Adv in Hem. 2016), although no randomized study so far has been conducted.Here, we retrospectively analyze the incidence and the characteristics of GVHD in the setting of HaploSCT using PT-Cy, after infusion of PBSC.Methods:Inclusion criteria were: adult pts with hematologic malignancies receiving a PBSC HaploSCT from 2012 to 2015 in 4 centers (3 in France and 1 in Italy) with PT-Cy as part of the GVHD prophylaxis.PBSC infusion at day 0 was followed by PT-Cy 50 mg/kg on days +3 and +4 in association with calcineurin inhibitors (cyclosporine A or Tacrolimus) and mycophenolate mofetil (MMF), started at day +5. All patients received G-CSF support from day+5 until neutrophil recovery.Study end points were the cumulative incidences of acute (a) and chronic (c) GVHD, with a specific organ grading evaluation, non-relapse mortality (NRM), relapse (CIR) as well as progression free (PFS) and overall survival (OS). Additionally, we analyzed the composite endpoint "GVHD and relapse free survival" (GFRS) for which the occurrence of relapse, death or severe chronic GVHD was considered as relevant events.Correlation between CD 34+ and CD 3+ and the incidence of aGVHD and cGVHD was studied by a linear continuous variable.Results:Between March 2012 and December 2015, 192 pts with a median age of 57 years (range: 16-73) received T-cell replete PBSC HaploSCT for hematologic malignancies (myeloid: n= 55%; lymphoid: n=45%) in 4 centers.Patient’s characteristics are shown in table 1. Pts received non myeloablative (according to Baltimore regimen) or busulfan-based reduced intensity conditioning, in 56% and 44% of cases, respectively. All, but 3 pts, engrafted, with a median time of 19 days (range, 14-47) to neutrophil recovery (ANC >500 x106/L) and 22 days (range, 14-252) to platelet recovery (PLT > 20 G x 109/L). The median CD34+ x 106/Kg and CD3+ x 106/Kg cells infused were 5.5 (range, 1.5-14.8) and 404 (range, 38-704), respectively. No relevant correlation was observed between the CD34+ and CD3+ infused cells and the incidence of GVHD, studied by linear continues variable. We noted only a trend to develop severe cGVHD with an increasing number of CD3+ cells infused. This result has to be considered with caution, because of the small events (6 pts affected by severe cGVHD).Complete donor T cell chimerisme was evaluable in 162 pts (83%) and achieved by day +30. The incidence of aGVHD was 38% at 100 days (all grades), whereas grade II-IV and III-IV were 24% and 10%, respectively. Concerning patients with aGVHD grade 2-4, the most affected organ was skin (19%), followed by gut (9%) and liver (2%). The incidence of 3-year cGVHD according to NIH classification was 15% (all grades).Three percent of pts developed severe cGVHD (lung n=1; liver, n=1). The most frequent involved organs were skin and mucosae (70%). No patient showed gut cGVHD. Finally, in univariate analysis, busulfan-based conditioning seems to negatively impact on severe cGVHD (p = 0.03; HR=3.37 [1.09 -10.46])After a median follow up of 20 (range, 4 - 52) months, NRM at 100 days and 1 year was 10% and 20%, respectively. Three-year OS, PFS, CIR and GRFS were 63%, 55%, 25% and 49%, respectively.Conclusion:This retrospective study shows a very low incidence of severe cGVHD after HaploSCT even with PBSC as stem cell source, suggesting that the use of PT-Cy may overcome the anticipated increased incidence of cGVHD, contrary to as previously reported in the HLA identical setting (Mohty et al. Leukemia 2003).Similar to HLA identical sibling and unrelated donor transplantation, the most frequent organs involved are skin and mucosae [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Androgens MAY BOOST Hematologic Response to ANTI-Thymocyte Globulin in Acquired Aplastic Anemia

Background:Androgens have shown encouraging results in the treatment of marrow failure, both in the animal model (Nouv Rev Fr Hematol. 1984, 26;391) and in patients with aplastic anemia (Blood. 1990;76: 2222). A first trial comparing ATG with or without androgens , failed to show improved response and survival in the androgens group (Blood. 1985; 66:184). However, in a second randomized trial , females receiving ATG+androgens had significantly superior response rates (BJH 1993,83:145). High dose ATG (twice the conventional dose) and androgens, was given to 87 patients, with 77% response rate and 78% survival at 5 years (Ann Hematol 2006;85:711). More recently sex hormones have been shown to increase telomerase activity, resulting in elongated telomeres in vitro [ Blood. 2009 114:2236), and in vivo [ N Engl J Med. 2016 19;374].Aim of the study: The aim of this study was to evaluate the outcome of androgen treatment in patients with Aplastic Anemia (AA) who had received a previous course of ATG and were persistently cytopenic.Patients and methods: 78 AA patients were selected as having received oral testosterone 40 mg/day 5-7 days/week , because of persistent cytopenia, in 1-3 cell lines. Typically testosterone was added to the ongoing treatment with cyclosporine. Median age was 37 years (9-72) ; there were 28 males and 50 females.. The median Hb level at start of testosterone, was 8.8 gr/dl( 3-14), the median neutrophil counts 1.7 x10^9/L (0.0-8) and the median platelet count 27x10^9/L (1-128). The median interval between ATG treatment and testosterone was 5 months (0-148); the median duration of androgen treatment was 517 days (range 122- 8984) . Patients were classified as non responders ( no hematologic improvement and/or transfusion dependent), partial responders (transfusion independent and improved peripheral blood counts), or complete responders (normalized peripheral blood counts).Result: Androgen treatment , at this relatively low dose, was well tolerated, with no abnormalities in liver function tests, and no apparent virilization. One patient discontinued testosterone because of intolerance (1,28%). Of the 78 patients treated, 33% (n=23) were classified as non responders, 29% (n=20) as partial responders and 38% (n=26) as completer responders.The median hemoglobin level at 90, 180 and 365 days after androgen therapy were respectively: 9.1; 10.6 and 11.4 g/dl; the median neutrophil counts were respectively 2.0; 2.0 and 3.0 x10^9/L; the median platelets were respectively 38, 54, 75 x10^9/L. There was therefore a gradual improvement of peripheral blood counts with time.With a median follow up of 871 days (range 27-8392), the actuarial 5 year survival, free from transplantation or a second course of immunosuppressive therapy, is 85% (Fig.1); it is 96% for responders and 45% for non responders (Fig2); fifteen out 23 non responders were allografted.Conclusion: The addition of androgen to cyclosporine , improved peripheral blood counts in 67% of our patients, who had failed, or partially failed first line therapy with ATG, with low or absent detectable toxicity. Our results confirm a role for androgens in patients with marrow failure, and this may be relevant for patients eligible for an unrelated transplant, or for older patients discussing an HLA identical sibling transplant. A 3 months course of androgens is still less hazardous as compared to an unrelated donor graft, and may offer the patient an opportunity to achieve transfusion independence without a graft. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Analysis of Clinical Efficacy and Prognosis in 83 Cases Receiving Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies

To summarize the clinical experience and evaluate the efficacy of haploidentical HSCT. The survival rates of 156 patients receiving either haploidentical (83 cases) or HLA-identical (73 cases) transplantation for hematologic diseases were compared and risk factors related to overall survival (OS) were analyzed. HLA-identical and haploidentical cohorts were not statistically different in the hematopoietic reconstitution, incidence of acute and chronic graft-versus-host disease (GVHD), OS, disease-free survival (DFS), relapse and treatment-related mortality (TRM) after transplantation. Multivariate analysis showed that advanced disease status, relapse and grade III-IV acute GVHD were independent prognostic indictors for OS with relative risk (RR) of 4.8 (95% CI 2.2-10.1), 4.3 (95% CI 2.6-8.0) and 3.3 (95% CI 1.6-7.0), respectively (P<0.05). Haploidentical transplantation with the present conditioning can achieve the therapeutic effects comparable to HLA-identical sibling transplantation. Disease status before transplantation and the presence or not of severe GVHD after transplantation have important significance for the long-term survival after transplantation.