Identical Sibling Donor Research Articles

NOVEL DRUG COMBINATIONS AND DONOR LYMPHOCYTE INFUSIONS ALLOW PROLONGED DISEASE CONTROL IN MULTIPLE MYELOMA PATIENTS RELAPSING AFTER ALLOGENEIC TRANSPLANT: New treatments for Multiple Myeloma patients relapsing after Allo transplant

BackgroundEven if allogeneic stem cell transplantation (allo-SCT) is curative for a minority of patients with multiple myeloma (MM), the patients who have relapsed after allo-SCT can experience long-term survival, suggesting a synergy between anti-myeloma drugs administered after allo-SCT and donor T cells. ObjectivesWe retrospectively evaluated the outcome of MM patients reported to the “Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare” (GITMO) network, who underwent allo-SCTs between 2009 and 2018 in order to identify predictors for long-term outcome in the whole population (242 patients) and for prolonged overall survival (OS) after relapse in the subgroup of relapsed patients (118 patients). ResultsAt a median follow-up of 40.9 months after allo-SCT median OS and progression free survival (PFS) of the whole population were respectively 39.4 and 19.0 months from allo-SCT. The cumulative incidence (CI) of non-relapse mortality (NRM) was 10.3 % at one year and 27.6% at five years. Grade 2-4 acute GVHD CI was 19.8% and 5-year CI of moderate or severe chronic GVHD was 31.8%. In the multivariate model older age at transplant (p=0.020), treatment with more than 2 lines of therapy before allo-SCT (p=0.003) and transplant from unrelated or haploidentical donor (p=0.025) were significant factors associated with reduced OS. Relapse after allo-SCT occurred in 118 (59%) patients at a median of 14.3 months (IQR 7.2-26.9). Twenty (17%) received only steroids, radiotherapy or supportive care, 41 (35%) received 1 line, 23 (19%) 2 lines and 34 patients (29%) 3 or 4 lines of salvage treatment. Nine patients were exclusively treated with chemotherapy, 9 received at least one salvage treatment including immunomodulating agents (Imids), 43 patients were treated with at least one rescue therapy including proteasome inhibitors (PIs) and 37 patients received at least one salvage treatment including monoclonal antibodies (33 daratumumab, 1 elotuzumab, 1 isatuximab, 2 belantamab). Median OS of relapsed patients was 38.5 months from allo-SCT and 20.2 months from relapse. In multivariate analysis, OS after relapse was significantly prolonged in patients with a longer time to relapse after allo-SCT (time to relapse 6-24 months p=0.016; time to relapse ≥ 24 months p< 0.001) and in those who had received at least 3 salvage treatment lines (p<0.036) and donor lymphocyte infusions (DLI) (p=0.020). ConclusionsIn our study, patients transplanted in early phases of disease and with HLA identical sibling donors had the best chance of long-term survival. Late relapse after allo-SCT, multiple courses of salvage treatment and the association with DLI could allow long disease control in patients who experienced relapse after allo-SCT.

Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical sibling donors for hematological malignancies in 6064 adults from 2003 to 2020: different impacts on survival according to time period

BackgroundMobilized peripheral blood stem cells (PBSC) have been widely used instead of bone marrow (BM) as the graft source for allogeneic hematopoietic cell transplantation (HCT). Although early studies demonstrated no significant differences in survival between PBSC transplantation (PBSCT) and BM transplantation (BMT) from human leukocyte antigen (HLA)-identical sibling donors to adults with hematological malignancies, recent results have been unclear. ObjectiveThe objective of this retrospective study was to compare overall survival (OS), relapse, non-relapse mortality (NRM), hematopoietic recovery and graft-versus-host disease (GVHD) between PBSCT and BMT according to the time period of HCT (2003–2008, 2009–2014, or 2015–2020). Study designWe retrospectively compared the outcomes after PBSCT versus BMT in 6064 adults with hematological malignancies using a Japanese registry database between 2003 and 2020. ResultsThe adjusted probability of OS was significantly higher in BMT recipients compared to PBSCT recipients during the early period of 2003–2008 (adjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.70–0.91; P < 0.001) and the middle period of 2009–2014 (adjusted HR, 0.80; 95% CI, 0.70–0.91; P < 0.001). However, during the late period of 2015–2020, the adjusted probability of OS was comparable between BMT and PBSCT recipients (adjusted HR, 0.94; 95% CI, 0.79–1.13; P = 0.564), which were mainly due to the reduction of NRM. There was no significant difference in the relapse rate between the groups, irrespective of the time period. Compared to BMT, PBSCT led to faster neutrophil and platelet recovery and the cumulative incidences of grades II–IV and grades III–IV acute and overall and extensive chronic GVHD were significantly higher in PBSCT recipients, irrespective of the time period. ConclusionsPBSCT and BMT had similar survival outcomes and relapse rates in adult patients with hematological malignancies during the late time period of 2015–2020 despite the hematopoietic recovery and acute and chronic GVHD being higher in PBSCT recipients in all time periods.

Risk factors and predictive model for mortality in patients undergoing allogeneic hematopoietic stem cell transplantation admitted to the intensive care unit.

Hematological malignant tumors represent a group of major diseases carrying a substantial risk to the lives of affected patients. Risk factors for mortality in critically ill patients have garnered substantial attention in recent research endeavors. The present research aimed to identify factors predicting intensive care unit (ICU) mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, the present study analyzed and compared the mortality rate between patients undergoing haploidentical hematopoietic stem cell transplantation (Haplo-SCT) and those undergoing identical sibling donor (ISD) transplantation. A total of 108 patients were included in the present research, 83 (76.9%) of whom underwent Haplo-SCT. ICU mortality was reported in 58 (53.7%) patients, with the values of 55.4 and 48.0% associated with Haplo-SCT and ISD, respectively (P=0.514). The mortality rate of patients undergoing Haplo-SCT was comparable to that of patients undergoing ISD transplantation. The present study found that reduced hemoglobin, elevated total bilirubin, elevated brain natriuretic peptide, elevated fibrinogen degradation products, need for vasoactive drugs at ICU admission, need for invasive mechanical ventilation and elevated APACHE II scores were independent risk factors for ICU mortality. Among patients presenting with 5-7 risk factors, the ICU mortality reached 100%, significantly exceeding that of other patients. The present research revealed that ICU mortality rates remain elevated among patients who underwent allo-HSCT, especially those presenting multiple risk factors. However, the outcome of patients undergoing Haplo-SCT were comparable to those of patients undergoing ISD transplants.

Quality-adjusted time without symptoms or toxicity analysis of haploidentical-related donor vs. identical sibling donor hematopoietic stem cell transplantation in acute myeloid leukemia.

We aimed to compare the quality-adjusted time without symptoms or toxicity (Q-TWiST) in acute myeloid leukemia (AML) patients who received haploidentical-related donor (HID) and identical sibling donor (ISD) hematopoietic stem cell transplantation (HSCT). Five clinical health states were defined: toxicity (TOX), acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD), time without symptoms and toxicity (TWiST) and relapse (REL). The equation used in this study was as follows: Q-TWiST=UTOX × TOX + UTWiST × TWiST + UREL × REL + UaGVHD × aGVHD + UcGVHD × cGVHD. A total of 239 AML patients were enrolled. We established a mathematical model, i.e., Q-TWiST HID HSCT > Q-TWiST ISD HSCT, to explore the range of utility coefficients satisfying the inequality. Based on the raw data, the utility coefficient is equivalent to the following inequality: [Formula: see text][Formula: see text]. The model showed that when [Formula: see text], [Formula: see text], and [Formula: see text] were within the range of 0-1, as well as when [Formula: see text] was within the range of 0-0.569, the inequality Q-TWiST HID HSCT > Q-TWiST ISD HSCT was valid. According to the results of the ChiCTR1800016972 study, the median coefficients of TOX, acute GVHD (aGVHD), and cGVHD were 0.56 (0.41-0.76), 0.56 (0.47-0.72), and 0.54 (0.37-0.79), respectively. We selected a series of specific examples of the coefficients, i.e., [Formula: see text]=0.5, [Formula: see text]=0.05, [Formula: see text]=0.5, and [Formula: see text]=0.5. The Q-TWiST values of ISD and HID HSCT were 896 and 900 d, respectively (P=0.470). We first observed that Q-TWiST was comparable between AML patients receiving HID HSCT and those receiving ISD HSCT.

Impact of COVID-19 in Thalassemia Patients Undergoing Hematopoietic Stem Cell Transplant Recipients

Objective: This article primarily examines the clinical attributes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in transplant recipients with thalassemia, offering significant insights into the treatment and care of this patient population. Method: The present study retrospectively analyzed the data of all thalassemia patients who underwent Hematopoietic stem cell transplantation (HSCT) at the First Affiliated Hospital of Guangxi Medical University between December 2019 and December 2022. A total of 280 patients were included, of which 81 had confirmed coronavirus disease 2019 (COVID-19). The study collected information on patient demographics, transplantation type and timing, graft-versus-host disease (GVHD), use of immunosuppressive agents, onset time and severity of COVID-19, and prognosis. Follow-up was conducted until March 31, 2023.Univariate analysis was performed using SPSS v25.0, and GraphPad Prism was used for the cumulative incidence comparisons. Results: The median age was 3.6(2-19) years.The main type of thalassemia was β type (93.9%). Identical sibling donors accounted for 40%, haploidentical donors accounted for 25.4%, and identical unrelated donors accounted for 34.6% (10/10). The main source of hematopoietic stem cells was bone marrow combined with peripheral blood (85%).There were no significant differences in age, gender, diagnosis, donor type, graft type, use of immunosuppressive agents, GVHD, and pneumonia of pro-COVID-19 between infected patients and non-infected patients with SARS-CoV-2. Most of the patients were mild (74 cases, 91.3%) in terms of the severity of COVID-19 infection, only 8.6% of the moderate cases, and none severe and died. 74 cases were cured without drug treatment. Of the seven patients treated with medications, four were azvudine and three were nematasvir. The median number of days (IQR) of treatment for COVID-19 was 5(5) days. The cumulative incidence in the immunosuppressive group was higher than that in the non-immunosuppressive group over the same time frame. There was no significant difference in the final infection rate of COVID-19 among patients receiving transplantation in different years(2020,2021,2022), which was 24.7 26.8 36.5 ( p=0.368), respectively. Conclusion: The low infection rate and no severe cases may be due to scientific protection and timely medication. There are no special risk factors for COVID-19 infection in thalassemia patients after transplantation.

Comparison of Outcomes of Hematopoietic Cell Transplantation (HCT) for Asymptomatic Patients with Sickle Cell Disease (SCD) and That of Propensity Matched Symptomatic Patients Undergoing HCT

Introduction Hematopoietic cell transplantation (HCT), a potential curative option for sickle cell disease (SCD) has typically been offered to patients with severe disease manifestations. With improved outcomes, especially in young children receiving HCT from HLA identical donors, some clinicians are performing HCT for patients without severe manifestations. HCT is associated with risk of substantial short-term morbidity, death, and long-term sequelae. Performance of HCT in patients who have not yet suffered from complications of SCD, raises unique issues of cost-benefit tradeoff, ethics, and healthcare equity. Further, it is unknown whether patients who have not suffered complications of SCD would have better outcomes following HCT. The objective of this study was to compare the outcomes for asymptomatic patients in patients undergoing HCT for SCD and propensity matched symptomatic SCD patients undergoing HCT. Methods: We queried the HCT for SCD dataset of patients undergoing HCT between 1990-2022 and reported to the Center for International Bone Marrow Research (CIBMTR) registry. Transplant essential data had been submitted for all patients while a subset of patients was assigned to the comprehensive research form (CRF) track. On these patients HCT centers submitted detailed SCD specific baseline data, as well as outcomes relevant to SCD and organ specific complications. The main reason for HCT is one of the variables collected in the CRF. Thus, we selected patients in the CRF track for further study. We describe demographics, baseline characteristics, transplant essential outcomes including overall survival (OS) and event free survival (EFS), graft failure (GF), Acute graft versus host disease (aGVHD) and chronic GVHD (cGVHD), venocclusive disease of the liver (VOD), post-transplant pneumonia/acute chest syndrome or other pulmonary complications(ACS), nephropathy, stroke, avascular necrosis (AVN), vasocclusive crises (VOC). We created a propensity score model, adding baseline variables. For each categorical outcome variable, frequency tables and tests of difference in proportions were derived. Descriptive statistics and tests of difference in means were derived for the two numeric outcome variables. In addition, survival analysis (Cox regression modeling) was conducted to determine the time until an individual experienced graft failure or death and whether event rates were associated with group classification adjusting for age and donor type. Results: For the entire cohort of 1718 patients undergoing HCT from 1990 to 2022 patients were followed for a median 47.8 months (0.3-312.9), 73.4% of patients with age at HCT &amp;lt;18 years and 74.7% with Karnofsky-Lansky score ≥ 90. The 3-year OS was 91.2%, 3-year EFS 75.5%, and GF rate was 17.9%, aGVHD grades II-IV occurred in 18.3%, and cGVHD developed in 22.3%. A total of 763 patients were assigned to the CRF track. The main reason for HCT was reported for these patients, and 49 patients were reported to be asymptomatic at baseline. In the asymptomatic patients majority of the HCT were performed for patients under the age of 10 years (n = 33) in patients with Hemoglobin SS (n = 45) and most occurred between 2013-2018 (n = 24). Average follow up period was 48 months. The most common graft source and conditioning regimens utilized were bone marrow (n = 35) HLA identical sibling donor type (63.2%, n = 31), and reduced intensity conditioning (n = 25) respectively. Other donor types included HLA mismatched relative (n = 9), mismatched unrelated donor and cord blood (n = 5), and matched unrelated was used in 4 patients. There was one death, at 16.5 months with cGvHD. GF occurred in 14.3%, OS was 97.9%, EFS 83.67%, 20.4% developed aGvHD and 28.5% developed cGvHD and none developed secondary malignancies or post-transplant lymphoproliferative disorders. Propensity matched control group (Figure 1) was constructed based on age at HCT, donor type, graft type, HCT comorbidity index, SCD type. There was good variable balance with a small standardized mean difference for matched observations. There were no statistically significant differences in least mean squares for EFS, death, OS, GF, AGVHD, CGVHD, VOD, VOC, AVN, stroke or ACS between the propensity matched groups ( Figure 1). Discussion: Complications and outcomes of HCT in asymptomatic patients with SCD patients is similar to that in propensity matched symptomatic SCD patients undergoing HCT.

Hematopoietic stem cell transplantation in patient with DOCK8 deficiency: Ukrainian experience

Dedicator of Cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency that exemplifies the broad clinical features of primary immunodeficiencies (PIDs), extending beyond recurrent infections including atopy, autoimmunity, and cancer. Purpose - to describe the natural course of hyper-IgE syndrome (HIES) disease in an 8-year-old boy and his path to diagnosis, as well as our first local history of conservative treatment for 6 months. In particular, we describe the effectiveness of omalizumab, and the application of allogeneic hematopoietic stem cell transplantation with follow-up. Clinical case. The 8-year-old boy presented with severe eczema and an involvement of the whole surface of the body. Infectious syndrome manifested from the age of 4 months in a form of recurrent respiratory infections. Over the next few years, the child suffered from life-threatening infections with high serum IgE (&gt;3000 IU/ml). The examination revealed a cushingoid constitution, flat-valgus feet, and dysmorphic features. Therefore, HIES was suspected. Genetic studies have confirmed the diagnosis by detecting a pathogenic homozygous mutation in the DOCK8 gene (Deletion Exons 2-46). We decided to use a humanized monoclonal anti-IgE antibody (off-label) to control the skin syndrome rather than systemic steroids. A significant improvement in skin condition, a decrease in eosinophils, and IgE were observed. Allogeneic stem cell transplantation of hematopoietic cells (HSCT) derived from peripheral blood of an human leukocyte antigen (HLA) - identical sibling donor was performed. The donor had a pathogenic mutation identical to the recipient in the DOCK8 gene but in a heterozygous state. Our data and treatment approach may be clinically useful as a diagnostic and treatment approach to HIES. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies No conflict of interests was declared by the authors.

Efficacy and Safety of Allogenic Hematopoietic Stem Cell Transplant in Paroxysmal Nocturnal Hemoglobinuria: A Single Centre Study from Pakistan

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of clonal hematopoiesis1 .The resulting abnormalities in complement regulatory proteins can manifest as hemolysis, thrombosis, and marrow failure2. The management and clinical outcomes of patients with PNH significantly changed with the development of complement inhibitor therapies3. Allogenic Hematopoietic stem cell transplant (HSCT) despite being the sole curative option for PNH is not recommended as first line therapy owing to its toxicities 4,5. Current indications for HSCT include a suboptimal response to eculizumab, severe AA/PNH, clonal evolution to myelodysplastic syndrome (MDS), or acute myelogenous leukemia2. However, in low and middle income countries (LMIC) where complement inhibitor therapies are not available, allogenic HSCT still remains the only treatment option for classical PNH as well as for PNH in the setting of another specified bone marrow disorder. Objective: To analyze the efficacy and safety of Allogenic HSCT in patients with paroxysmal nocturnal hemoglobinuria (PNH). Study design: Observational, retrospective study. Place and duration of study: Armed Forces Bone Marrow Transplant Centre/ National Institute of Blood and Marrow Transplant (AFBMTC/NIBMT) Rawalpindi, Pakistan, from June 2008 till February 2022. Methodology: From June 2008 till February 2022, a total of 65 patients of PNH were registered at AFBMTC/NIBMT. Out of these16 patients underwent allogenic HSCT and were included in the final retrospective analysis. PNH diagnosis was confirmed by flow cytometry by the demonstration of GPI-negative cells in at least two cell lineages i.e neutrophils, red blood cells (RBCs) in 62.5% (n=10) patients and by fluorescent aerolysin (FLAER)-based assay in 37.5% (n=6) patients. Median time from diagnosis to transplant was 380 days. All patients received HLA identical sibling donor HSCT. Stem cell source was Bone marrow harvest (BMH), BMH plus peripheral blood stem cell (PBSC) and PBSC alone in 81% (n=13), 12.5% (n=2) and 6% (n=1) patients respectively. Graft versus host disease (GVHD) prophylaxis was with Antithymocyte globulin (ATG) + Cyclosporin (CSA) in patients receiving NMA conditioning or ATG + CSA + short term Methotrexate (MTX) in those receiving MAC. Results: Median age of the study cohort was 24 years (range, 18 to 42 years) and all were male. 68.7% (n=11) patients received immunosuppressive therapy before HSCT with partial or no response. History of thrombosis prior to HSCT was present in only one patient (cPNH). Allogenic HSCT done for classical PNH (cPNH) in 75% (n=12) patients and for PNH in the setting of another specified bone marrow disorder (PNH/AA) in 25% (n=4) patients. Patients with classical PNH received Myeloablative conditioning (MAC) i.e Flu150Bu12.8IV (75%, n=9), Bu16Cy120 (8.3%, n=1), or Flu150Cy200 (8.3 %, n=1) except for one patient who received Flu150Cy160. Patients with PNH/AA, received non myeloablative conditioning (NMA) i.e Flu150Cy120, except for one who received Flu150Bu12.8IV. Out of 16 patients, 94% (n=15) patients achieved successful engraftment with full donor chimerism. One patient (cPNH) had Primary graft failure. Median time to neutrophil and platelet engraftment was day +12 and day +22 respectively. Disease relapse was monitored by donor chimerism till Day +180 post BMT and thereafter by peripheral blood counts. PNH clone post BMT was not tested. Incidence of acute GVHD grade I/II involving skin and gut, was 25% (n=4). No incidence of chronic GVHD was noted. One patient (PNH/AA) had secondary graft failure on Day +46. With a median post-transplant follow-up of 15 months (range, 4 to 157) overall survival (OS) was 93.7% and disease-free survival (DFS) was 87.5%. Conclusion: In resource constrained, LMIC, where complement inhibitor therapies are currently unavailable, allogenic HSCT remains the valid option for treatment of PNH, with good overall survival rate and acceptable treatment related toxicites. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Poster: CT-132 Outcome of Sex-Mismatched Allogeneic Hemopoietic Stem Cell Transplantation from Human Leukocyte Antigen–Identical Sibling Donors in Patients With Hematologic Diseases

Poster: CT-132 Outcome of Sex-Mismatched Allogeneic Hemopoietic Stem Cell Transplantation from Human Leukocyte Antigen–Identical Sibling Donors in Patients With Hematologic Diseases

CT-132 Outcome of Sex-Mismatched Allogeneic Hemopoietic Stem Cell Transplantation from Human Leukocyte Antigen–Identical Sibling Donors in Patients With Hematologic Diseases

Hematopoietic stem cell transplantation is a procedure aiming to cure hematologic diseases. However, graft-versus-host disease (GVHD) and disease relapse/failure are common side effects of this treatment. Sex-mismatched transplantation, particularly with female donors and male patients, is known to be associated with higher incidence of GVHD or lower incidence of survival. This is caused by the antibodies against minor histocompatibility antigens found on the Y chromosome of the male recipient, which were found to be associated with increased risk of chronic GVHD and non-relapse mortality. The study aimed to determine the incidence of acute and chronic GVHD, overall survival, and non-relapse mortality when male patients received stem cells from female matched sibling donors in allogeneic hematopoietic stem cell transplantation. Retrospective study over 8 years. Nasser Institute Hospital. In this study, patients were divided into 2 groups. Group 1: female donors to male patients (245 patients). Group 2: male donors to female patients (186 patients) and same-sex donors and patients (506 patients). The median age was 20 years (7 months-60 years). The outcome of transplants in the female-to-male group was compared with that of the male-to-female and same-sex group. Overall survival, incidence of acute and chronic GVHD, non-relapse mortality, and relapse/failure rate. Overall survival was 68.6% in group 1 compared to 69.5% in group 2 (P=0.5). Acute GVHD was 24% in group 1 compared to 19.6% in group 2 (P=0.1). Chronic GVHD was 15.1% in group 1 compared to 9.6% in group 2 (P=0.02). Non-relapse mortality was 27.7% in group 1 compared to 25.7% in group 2 (P=0.5). Relapse/failure rate was 4.9% in group 1 compared to 6.5% in group 2 (P=0.3). Allogeneic stem cell transplantation for male patients from female donors can be associated with a significantly higher rate of chronic GVHD but a lower incidence of relapse/failure.

Clinical and healthcare burden of disease associated with cytomegalovirus in allogeneic hematopoietic stem cell transplantation - A retrospective single-center study.

CMV infection is a common complication in allogeneic hematopoietic stem cell transplantation (HSCT). We investigated the association of clinically significant CMV (CS-CMV) infection with clinical outcomes and healthcare resource utilization in allogeneic HSCT patients in Finland. This retrospective study included adult patients who received their first allogeneic HSCT between January 1, 2013, and December 31, 2018, at the Turku University Hospital. Data were collected from the hospital data lake. Clinical and healthcare outcomes were investigated at one year and mortality up to three years. The study included 251 patients. CMV seroprevalence was 69.7%. CS-CMV infection occurred in 59.0% of the patients, and of those, 14.2% had ≥2 infections. The median time to CS-CMV infection was 34.5 days (Q1 -Q3 , 27.0-45.0). Recipient and donor seropositivity, and lymphoproliferative diseases were associated with higher, and HLA identical sibling donors with lower CS-CMV infection risk. CS-CMV infection was not associated with mortality in three years of follow-up. One hundred thirty-three (89.8%) and 75 (72.8%) patients with and without CS-CMV infection, respectively, were readmitted to the hospital. Patients with CS-CMV infection had more hospital readmissions (incidence rate ratio [IRR] 1.38, 95% confidence interval [CI] 1.10-1.73, p = .005) and patients with one CS-CMV infection (IRR 1.48, 95% CI 1.12-1.94, p = .005) or ≥2 infections had longer length of hospital stay (IRR 2.71, 95% CI 1.76-4.35, p<.001). CMV seroprevalence is relatively high among Finnish allogeneic HSCT patients. CS-CMV infection was common and associated with a higher readmission rate and longer length of hospital stay.

On High-Dimensional Covariate Adjustment for Estimating Causal Effects in Randomized Trials with Survival Outcomes.

The purpose of this work is to improve the efficiency in estimating the average causal effect (ACE) on the survival scale where right-censoring exists and high-dimensional covariate information is available. We propose new estimators using regularized survival regression and survival Random Forest (RF) to adjust for the high-dimensional covariate to improve efficiency. We study the behavior of the adjusted estimators under mild assumptions and show theoretical guarantees that the proposed estimators are more efficient than the unadjusted ones asymptotically when using RF for the adjustment. In addition, these adjusted estimators are - consistent and asymptotically normally distributed. The finite sample behavior of our methods is studied by simulation. The simulation results are in agreement with the theoretical results. We also illustrate our methods by analyzing the real data from transplant research to identify the relative effectiveness of identical sibling donors compared to unrelated donors with the adjustment of cytogenetic abnormalities.

P3.01: Similar Graft-Versus-Host Disease (GVHD) Incidence Among Unrelated and Identical Sibling Donor Transplantation With the Use of Anti-thymocyte Globulin (ATG)

Introduction: GVHD is the main cause of morbidity and mortality associated with allogeneic hematopoietic stem cell transplantation (HSCT) with an incidence rate of 40-60%. Addition of ATG has shown to reduce its incidence. We report the GVHD outcomes with the use of ATG as part of the prophylaxis regimen in a group of patients (pts) undergoing HSCT. Methods: From March 2018 to June 2021 we conducted a prospective multicenter study including 95 consecutive pts.: 33 transplanted with an identical sibling donor (ISD), 33 with an HLA-matched unrelated donor(MUD) and 18 with an HLA 1 miss-matched donor (MMUD). Conditioning regimen was according to institutional protocol. GVHD prophylaxis included tacrolimus and methotrexate plus ATG (Timoglobulina®Sanofi) 2.25 mg/kg days -3 and -2. GVHD incidence, relapse and death were recorded. Acute GVHD (aGvHD) and chronicGVHD (cGVHD) were defined using Glucksberg criteria and NIH clinical grading respectively. Median and interquartile range (IQR) were used to describe non-parametric data, group comparison with X2, Kaplan Meyer curve and multi-sample log Rank test for survival analysis, considering a statistically significant p value of less than 0.05. Results: 42 pts were male and donors were female in 56% (n:54). Conditioning regimen was myeloablative in 81% (n:77). Median time to neutrophil and platelet engraftment were 17 days (range 15-21) and 17 days (range 12-20) respectively. 6/95 pts presented graft failure. aGVHD incidence was 36% (n:34), grades I-II 19% (n:19) and III-IV 16% (n:15). Incidence of grades III-IV did not varied according to donor: 15% (n:7) for ISD, 9% (n:3) for MUD and 27% (n:5) for (X2 3.06, p0.21) Overall incidence of cGVHD was 23% MMUD (n:21): Grades mild 6% (n:6), moderate 11% (n:11) and severe 4% (n:4). According to donor type, severe cGVHD was 2% (n:1), 3% (n:1) and 11% (n:2) using ISD, MUD and MMUD respectively (X2 2.65, p0.26). At one year, 15/79 pts (19%) were under immunosuppressive treatment. Transplant related mortality at day 100 was 9% (n:9). Most frequent cause was sepsis (n:4). In 31 pts CMV reactivation was detected (more than one reactivation in 6 pts of which 5 had GVHD) and 7 reactivated EBV infection. None evolved to PTLD. Median follow-up time was 524 days (IQR 168-833). cGVHD–free and relapse-free survival (combined endpoint) at 1 year was 57% (n:54) of 79 evaluables patients. cGVHD and relapse free survival at 1 year was 48% for IDS (33-63%CI), 66% for MUD (47-81%CI) and 38% for MMUD (21-60%CI). No significant difference was found according to donor type (X2 4.98; p0.083). Conclusion: With the use of ATG no difference was observed in the incidence of aGVHD grades III-IV and severe cGvHD between the different types of donor. This results should be confirmed with a higher level of evidence study.

Immune tolerance induced by hematopoietic stem cell infusion after HLA identical sibling kidney transplantation.

After the first attempt to induce operational tolerance, it has taken decades to implement it in clinical practice. Recipients with Human leukocyte antigen (HLA) identical sibling donors were enrolled. Hematopoietic stem cells (HSCs) infusion was done after HLA identical sibling kidney transplantation (KTx). Three cases included were followed up for over 8 years. The perioperative conditioning protocol included anti-CD20, rabbit anti-thymocyte globulin (ATG), total lymphoid irradiation (TLI), and cyclophosphamide. Infusion of CD3+ cells and CD34+ cells was conducted. The withdrawal of immunosuppression was determined by mixed lymphocyte reaction (MLR) and graft biopsy. Case 1 and Case 2 showed persistent chimerism, while chimerism was not detected in Case 3. All three recipients showed a low-level response to donor-specific stimulation. Case 1 and Case 3 met the withdrawal rules at 16 and 32 months after transplantation, respectively. Graft function was stable, and no rejection signs were observed in routine biopsies until 94 and 61 months after transplantation. Case 2 was diagnosed with graft-versus-host disease (GVHD) 9 months after transplantation and recovered after an enhanced immunosuppression therapy. Steroids were withdrawn after 1 year, and 0.5 mg tacrolimus twice a day is currently the only immunosuppression at 8 years and 8 months. In conclusion, our clinical experience indicated the efficacy of non-myeloablative conditioning protocol for tolerance induction in HLA identical patients. Complete chimerism might be a risk factor for GVHD.

Clinical significance of low pre-transplant donor specific antibodies (DSA) in living donor kidney recipients with negative complement-dependent cytotoxicity crossmatches (CDCXM), and negative flow cytometry crossmatches (FLXM) – A single-center experience

BackgroundIt is controversial whether all donor-specific antibodies (DSA) detected by the solid-phase single antigen bead (SAB) assay negatively affect kidney transplantation outcomes. The study aimed to evaluate the possible clinical significance of low pre-transplant DSA in living donor kidney recipients. We analyzed a group of patients with HLA-A, B, and -DR DSA reactivities below a virtual crossmatch (VXM) value of 5000 MFI but with all VXM DSA reactivities at HLA-DQ, -DP, and -Cw, which were not typed routinely for donors prior to transplantation. We also investigated the incidence of persistent and de novo DSAs in available posttransplant SAB assays. MethodsFrom the historical cohort of living donor recipients transplanted between 2014 and 2018 at our center (n = 82), 55 patients met the inclusion criteria, namely: these patients were > 18 years old with non-HLA identical sibling donors, who were not desensitized, who had available pre-transplant SAB results, and who had negative both complement-dependent cytotoxicity crossmatch (CDCXM) and flow cytometry crossmatch (FLXM) results. An additional donor HLA typing, performed for all 55 recipients, identified donor additional HLA-DQ, -DP, and -Cw DSA reactivities. These patients were then divided by SAB reactivity into three groups: 1) those with DSA-positive reactivities; 2) those with non-donor-specific anti-HLA reactivities (NDSA); and, 3) those who were anti-HLA-negative. All these recipients were followed for three years and checked for their de novo or persistent DSA. ResultsIn the studied cohort, DSA-positive, NDSA reactive, and anti-HLA negative recipients constituted 33%, 36%, and 31% of 55 patients, respectively. Non-routinely considered pre-transplant HLA-DQ, -DP, and -Cw DSA-positive reactivities were shown in as many as 78% of DSA-positive cases (group 1) with the lowest MFI value of 319 to DP4 and the highest MFI of 5767 to DQ2. Of the pre-transplant HLA-A, B, and -DR DSA reactivities, only -DR52 DSA reactivity reached the highest MFI value of 2191. These detected DSAs did not reduce the mean estimated glomerular filtration rate (eGFR) values and did not increase the incidence of proteinuria in recipients. While the 3-year graft survival was lower in the DSA-positive group (94.4%) with one recipient who lost kidney transplant, the difference was not significantly different (p = 0.7) from the NDSA (100%) and negative (100%) groups. In terms of the incidence of de novo acute antibody-mediated rejection (AMR) at three years after transplantation, no case has been reported in the cohort. This may suggest that low DSA-positive recipients do not experience higher rejection rate. However, DSA-positive recipients had a tendency for a higher frequency of C4d deposits in peritubular capillaries (PTC) and de novo DSA. ConclusionOur 3-year follow-up of patients with low pre-transplant DSA found no association with a deterioration in graft function and worse graft survival. Furthermore, we did not observe an increase in AMR in our patients with low DSA. A larger cohort and a longer follow-up period may be needed to evaluate the tendency of low DSA-positive recipients towards the higher incidence of C4d deposits in PTC and/or de novo DSA.

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

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

P1326: FACTORS ASSOCIATED WITH THE OUTCOME OF ALLO-HSCT FOR ADVERSE-CYTOGENETIC RISK ACUTE MYELOID LEUKEMIA

Background: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the unique intention-curative consolidation strategy in patients with Acute Myeloid Leukemia (AML) with unfavorable cytogenetic risk. It is a high-cost procedure with significant transplant-related mortality (TRM), therefore, the correct selection of candidates for allo-HSCT resembles as a crucial issue. Aims: To describe the outcome of this procedure and to identify those patients who could obtain a better benefit. The primary endpoint was Overall Survival (OS) and secondary endpoints were relapse-free survival (RFS), cumulative incidence of Graft-versus-host disease (GVHD), cumulative incidence of relapse and (TRM). Methods: We conducted an observational retrospective study in patients with adverse-risk cytogenetically defined AML (Upon the European LeukemiaNet 2017 criteria and the results of the Next Generation Sequencing) who underwent a first allo-HSCT in two tertiary referral centers between 2010 and 2020. Results: We analyzed 82 patients with a median age at the moment of transplant of 55 (R 22-73) years. The median time from diagnosis to transplant was 5 (IR 4-7) months. Forty-two (51,2%) were women. Twenty-six patients (31,7%) had an identical HLA sibling donor and 37 (45,1%) had an unrelated HLA identical donor. A myeloablative conditioning was performed in 60 (51%) patients and in 48 (59,8%) the source of HSC was bone marrow. The majority (81,7%) had a first complete remission (CR1) at the moment of transplant and 13,4% had a partial response or a refractory disease (PR/RD). The 41,5% patients had a low comorbidity index score (HCT-CI<3). With a median follow up of 36 months, the OS at 1 and 3 years was 67% (95% CI 64-66%) and 48% (95% CI 45-51%) respectively. The RFS at 1 and 3 years was 62% (95% CI 61-63%) and 45% (95% CI 43-47%), the cumulative incidence of relapse at 1 and 3 years was 18% (95% CI 11-28%) and 29% (95% CI 19-40%) and the TRM at 1 and 3 years was 21% (95% CI 13-30 %) and 28% (95% CI 19-39%) respectively. The cumulative incidence of acute GVHD grade III-IV at day +100 was 17% (95% CI 9-26%). The cumulative incidence of moderate-severe chronic GVHD at 1 and 3 years was 21% (95% CI 13-30 %) and 31% (95% CI 21-42%) respectively. There were no differences in OS regarding age (p=0,2), sex (p=0,9), HCT-CI score (p=0,7), type of donor (p=0,4), acute GVHD (p=0,5), HSCT source (p=0,06), conditioning (p=0,04) and subtype of ELN2017 (p=0,9). A worse OS was observed in patients with PR/RD (HR 1,5 95% CI 1,2-1,9) (p<0,01) compared to those in first complete remission. The OS at two years was 28% (95% CI 26-30) and 59% (95% CI 58-60) respectively (Figure 1). Sixty-six patients were analyzed for OS depending on the development of cGVHD. The OS at 2 years of the patients who did not develop cGVHD (n= 32) was 58% (95% CI 56-60) of those with a mild cGVHD (n=10) was 85% (95% CI 83-87) of those with a moderate cGVHD (n=15) was 79% (95% CI 77-81) and of those who develop a severe cGVHD (n=9) was 64% (95% CI 61-67). Therefore, a worse OS was observed in patients who did not develop cGVHD or had a severe grade compared to those who had a mild or moderate cGVHD HR 5 (95% CI 1,8-15) (p<0,01). Image:Summary/Conclusion: In our series, Allo-HSCT in adverse-cytogenetic risk AML are associated with better OS when it is performed in first complete remission and its benefit is unclear performed in partial response or in a refractory disease, where other strategies should be considered. The development of mild or moderate cGVHD was associated with a better overall survival.

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

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

Pediatric hematopoietic stem cell transplantation in Serbia - 25 years of experience

The first allogeneic identical sibling donor hematopoietic stem cell transplantation at the Institute for Mother and Child Health Care of Serbia ?Dr. Vukan Cupic? (Institute) was performed in the seventies of the last century. Almost twenty years later, the first allogeneic transplant from sibling haploidentical donor was performed in an infant suffering from severe combined immunodeficiency. After several years of efforts, the bone marrow transplant unit was opened in April 1997 at the Institute. Over the 25 years, the transplant team performed 360 hematopoietic stem cell transplantations, 175 autologous and 185 allogeneic (103 from identical sibling donor, 43 from haploidentical sibling donor, 36 from matched unrelated donor, 2 from identical sibling cord blood and 1 from unrelated identical cord blood).

Haploidentical Stem Cell Transplantation in Patients with Myelodysplastic Syndrome: Case Report First Experience

&#x0D; BACKGROUND: Allogeneic stem cell transplantation (ASCT) is a potentially curative therapeutic approach in patients with intermediate and high-risk myelodysplastic syndrome (MDS). If a family sibling or unrelated donor is not available mismatched donors are viable option for young patients with no comorbidities. The aim of this case presentation was to evaluate our first experience with haploidentical transplantation for this indication.&#x0D; CASE PRESENTATION: We present a case of 50 years male patient with myelodysplastic syndrome (MDS) diagnosed at University Clinic for hematology, Skopje, North Macedonia. Patient was scored in IPSS -R as high risk patient. He was referred for HLA DNA typing of family siblings and since he didn’t have identical sibling and unrelated donor, he was referred to continue treatment with haploidentical stem cell transplantation. He received Flu Bu conditioning and PTCY, cyclosporine and MMF for GVHD prophylaxis. Peripheral blood stem cells (PBSC) from his mismatched brother were infused in the amount of CD34=5.8x106/kg. He experienced prolonged engraftment, severe infective bacterial infections and CMV reactivation with clinical manifestation of CMV colitis. He was successfully treated with antiviral drug and completely resolved. His bone marrow analysis showed complete remission and chimerism evaluation revealed high donor engraftment. Patient is now +34 months post transplant in complete remission.&#x0D; CONCLUSION: The use of a mismatched donor increases the risk of NRM, but there is also evidence to suggest that an haploidentical donor is a valid choice, as general outcome appears to be at least similar to MUD.