Presence Of Acute GVHD Research Articles

THE ROLE OF THERAPEUTIC DRUG MONITORING OF INTRAVENOUS BUSULFAN FOR PREVENTION OF SINUSOIDAL OBSTRUCTION SYNDROME IN CHILDREN

Busulfan is a widely used alkylating drug for conditioning of hematopoietic stem cell transplantation (HSCT). Higher exposure of Bu is associated with toxicity and (sinusoidal obstruction syndrome) SOS, whereas lower exposure is associated with graft failure or relapse risk. Therapeutic drug monitoring (TDM) has been recommended to overcome these issues. We aimed in this study to compare HSCT outcomes in children with and without TDM of Bu. This retrospective study conducted at our Transplantation Unit between 2012 and 2021. Patients aged 0-18 y underwent HSCT who received Bu-based conditioning and completed post-transplant +100 days included in the study. Data were collected including demographic information, primary diagnoses, conditioning regimen, graft-related data, dose of Bu, time to neutrophil and platelet engraftment, presence of SOS, acute or chronic GvHD, and clinical outcomes. SPSS 18.0 was used for statistical analysis. 172 patients (59 girls, 113 boys) with a median age of 4.70 years (IQR 2.41-10.01) were enrolled in the study. TDM of Bu was performed in 126 patients. 32 patients (19%) developed moderate or severe SOS. Incidence of SOS was significantly higher in the group without TDM. A multivariable analysis showed that presence of acute GVHD and 2 or more alkylating agents in conditioning regimen were associated were SOS. HSCT related outcomes, relapse, OS and EFS did not different between two groups. To improve treatment outcomes of Bu, TDM and dose adjustment, following the first dose, has highly recommended regardless of the dosing guideline was used. We also demonstrated the incidence of SOS decreased in patients with TDM, but other HSCT related outcomes were not influenced. Optimal cumulative Bu exposure canbalance between efficacy and toxicity of HSCT in children.

BK Virus Induced Haemorrhagic Cystitis in Haematopoietic Stem Cell Transplant Setting — a 10 Year Retrospective Case Control Study

INTRODUCTIONBK virus (BKV) is a human polyomavirus that usually causes asymptomatic or mild respiratory illness in childhood and thereafter remains latent in renal epithelial cells. With decreased cell-mediated immunity, reactivation of BKV causing haemorrhagic cystitis (HC) is a well-known complication of haematopoietic stem cell transplantation (HSCT) that is associated with increased morbidity, mortality, longer hospital stays and increased hospital costs. This analysis was done to ascertain etiological risk factors, incidence and outcomes of BKV induced HC following HSCT. METHODSIn this retrospective case control study of patients undergoing HSCT in the Department of Haematology at CMC Vellore between 2007 and 2016, we compared patients who developed BKV induced HC with those without BKV infection [controls] matched for age, diagnosis, conditioning regimen and donor source. Data was collected from individual medical records and databases maintained in the Departments of Haematology and Virology. The BKV PCR was designed as a real time PCR that targets the VP1 region of the BKV genome. Viral nucleic acid extraction was performed as recommended on the urine samples of these patients using the QIAamp DNA blood Mini kit (Qiagen, GMBH, Germany). Real-time PCR detection was performed as described previously. RESULTSThere were 1276 (120 haploidentical) transplants that were performed between 2007 to 2016. Two hundred and sixty two (20.5%) patients had HC and BKV qualitative PCR was performed for 189 patients, of which 105 were positive. Among the cases, males were more affected and the median age was 20 years. The most common indication for transplant was aplastic anemia (31.4%), followed by acute myeloid (19.0%) and lymphoblastic (15.2%) leukemia. Predominant conditioning regimens were myeloablative conditioning (57.1%) with reduced intensity conditioning being least common (8.6%). In the patients with HC, Grade 3 HC was most commonly (57.1%) seen and the median time to development of HC was 35 (range 0-858) days. Specific treatment with cidofovir was given to only 5 patients, surgical intervention in 2 patients and foscarnet in 1 patient. Acute GVHD was seen in 53.35%. HLA matched sibling (53.3%) donors, followed by 8 or 9/10 matched unrelated (16.2%) donors were most frequent. Survival was significantly lower in the cases (42.9% vs 61%, p=0.013). Protective effect of non myeloablative conditioning, residual disease at time of transplant, lower CD34 dose, presence of acute GVHD and chronic GVHD, reactivation of CMV and presence of bacterial urinary tract infections (UTI) were significant factors on univariate analysis. Multivariate logistic regression confirmed presence of acute GVHD, bacterial UTI and residual disease at time of transplant as significant risk factors for BK viruria and disease. CONCLUSIONBKV HC was seen in 8% of HSCT patients with mortality of 57.1%. Presence of acute GVHD, bacterial UTI and residual disease at time of transplant emerged as significant risk factors. DisclosuresSrivastava:Bayer Healthcare, Shire, Novo Nordisk, Roche Genentech, LFB: Other: Educational grants / Advisory Board / Grants Review / Data Monitoring Committee, Research Funding.

Mortality among pediatric hematopoietic stem cell transplantation patients: Report from a single center in southern Brazil.

HSCT has grown in number in recent years. This treatment in children has its particularities and has been characterized in previous studies only on a limited basis. There are important causes of morbidity and mortality in this group of patients, including evolution of primary disease, graft failure, infectious diseases, and GVHD. The aim of this study was to report case series of TRM within 100days after transplantation and associated factors. Retrospective cohort. All children transplanted between January 1, 2010 and December 31, 2017 were included and those who underwent the first HSCT in another center were excluded. Data from 292 children were analyzed. TRM in 100days was 5.8%, being significantly higher in patients with umbilical cord blood as the cell source. Infectious complications were frequent in this sample (bacterial infections in 27%, viral infections in 75.3%, and fungal infections in 12%) and both the presence of fungal disease and more than one infection during the follow-up (viral and bacterial, viral and fungal or bacterial and fungal) had statistically significant association with the outcome. The prognosis in allogeneic HSCT is influenced by the origin of the stem cells, the presence of acute GVHD and the occurrence of infectious diseases. Studies that evaluate pediatric individuals undergoing HSCT and analyze their mortality profile, can improve the management of these patients, possibly leading to a reduction in TRM.

Pre-transplant use of tyrosine kinase inhibitors and transplant associated thrombotic microangiopathy - a single centre analysis of incidence, risk factors and outcomes.

Transplant associated thrombotic microangiopathy (TA-TMA) is life-threatening complication post allogeneic stem cell transplant (ASCT). Risk factors and prognosis of TA-TMA are not well defined. We retrospectively studied consecutive ASCT patients with AML, ALL, and CML from January 2008 to March 2019 to study the incidence, risk factors, and outcomes of TMA. Definitive and probable TA-TMA was defined using Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) and Cho criteria, respectively. Risk factors explored were age, gender, diagnosis, type of transplant, use of tyrosine kinase inhibitors (TKI) pre transplant, conditioning regimen, and acute GVHD. Standard statistical methods were used. Total 241 patients, 179 (74.2 %) males, median age of 29 years were studied. Diagnoses were AML in 104, ALL in 85 (Ph+ve 23) and CML 52. Total 26 (10.7%) patients (22 males) developed TA-TMA at median of day+102. On multivariate analysis, pre-HSCT TKI (OR 2.7, p = 0.028), haplo-HSCT (OR 3.16, p = 0.018) and presence of acute GVHD (OR 4.17, p = 0.003) were significant risk factors. With a median follow up of 60 months, median OS with and without TA-TMA was 18 and 97 months respectively (p = 0.021). The association of pre-HSCT with TKI with TA-TMA merits further exploration in prospective studies.

Factors Affecting Post-Transplant Relapse of Acute Lymphoblastic Leukemia (ALL) in Children According on the Intensity of Conditioning

Background: Relapse of ALL remains the major cause of transplant failure. Relapse incidence after allo-HSCT is described in 30-40% of patients. Patients with ALL receive allo-HSCT with MAC more often because after RIC more relapses are expected. The aim: To compare the frequency of relapse after allo-HSCT with RIC vs with MAC and to analyze the factors influencing the risk of relapse depending on the intensity of conditioning regimens. Patients and methods: Between 12/2000 and 09/2019 at RM Gorbacheva Research Institute a total of 235 children with ALL (median age of 10 years (0,5-18), underwent allo-HSCT. MAC (busulfan- or treosulfan-based) were used in 163 pts: 1st CR - 30 pts (MRD+ n=13), 2nd CR - 58 pts, 3rd or 4 CR - 27 pts, relapse - 48 pts. Allo-HSCT with RIC were performed in 72 pts: 1st CR - 12 pts (MRD+ n=9), 2nd CR - 29 pts, 3rd or 4 CR - 14 pts, relapse -17 pts. RIC consisted of fludarabine (30 mg/m2/d x 5 days) + melphalan (70 mg/m2/d x 2 days) or fludarabine (30 mg/m2/d x 5 days) + busulfan (4 mg/kg/d x 2 days). Matched related allo-HSCT was performed in 37 pts (16%), matched unrelated - in 128 pts (54%), haploidentical-in 70 pts (30%). Cumulative incidence functions were used to estimate relapse incidence and NRM in a competing risk setting. Univariate analyses were performed using Grey test for cumulative incidences. Multivariate analyses were performed using the Cox proportional-hazard model. Results: Median follow-up was 5,4 and 4,5 years for МАС and RIC, respectively. Relapses were diagnosed in 105 pts (44%) during 1-39 months after allo-HSCT (median 7.5 months) (90% relapses were during first 18 mo), 74 pts after MAC; 31 pts after RIC (p=0,549). Relapses occurred significantly less frequent (p=0,007) in patients who had CR at the moment of allo-HSCT - 61 pts (35%) (RIC -32%; MAC -37%) compared patients who had a relapse or primary resistance 44 pts (68%) (RIC-74%; MAC - 65%). The risk of relapse after MAC is influenced by the presence of acute GVHD (p=0,007), the source of HSCs (PBSC vs BM, p=0,032), and the status of the disease (CR vs relapse) at the moment of allo-HSCT (p=0,001). The risk of relapse after RIC is influenced by the presence of acute GVHD (p=0,042), age at the moment of allo-HSCT 1-10 years (p=0,032), and the status of the disease (CR vs relapse) at the moment of allo-HSCT (p=0,001). Multivariable analysis confirmed a significant impact of disease status at the moment of allo-HSCT whit MAC (p=0,001) and with RIC (p=0,002). Presence of aGVHD was additional factor associated with lower relapse risk in multivariate analysis in pts after MAC (p=0,005). Patients with active disease at the moment of HSCT had higher relapse-free survival after RIC (RIC-23% vs MAC- 12%, p=0,012). Salvage patients in whom the relapse was documented after HSCT had 28% and 38% probability of long-term OS after RIC and MAC, respectively (p=0,572). Conclusion: Relapse incidence after allo-HSCT with MAC and with RIC is comparable. The most significant factor affecting the risk of relapse is the status of the disease at the moment of allo-HSCT. Disclosures No relevant conflicts of interest to declare.

Significant EBV Reactivation Is Associated with Poorer Overall Survival Due to Increased NRM Post Myeloablative/Reduced Intensity, T-Cell Deplete Allogeneic Stem Cell Transplant for MDS or Acute Leukaemia

Introduction EBV reactivation post allogeneic stem cell transplantation (alloSCT) occurs due to profound suppression of T-cell number or function and subsequent reactivation of latent host or recipient EBV infection through loss of immune-surveillance. The relationship of EBV reactivation to patient outcomes has not been reported in patients who have received T-cell depletion (TCD) with Thymoglobulin. This analysis assessed the outcomes in patients who had previously received an alloSCT with TCD using Thymoglobulin and who developed EBV reactivation that either required treatment (EBV Treatment) vs those who did not require treatment (EBV No Treatment) vs those who had no evidence of EBV reactivation (No EBV). Methods This was a retrospective review of all patients who received TCD with Thymoglobulin prior to alloSCT at the Royal Melbourne Hospital between 2006-2017. Eligible patients received reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) for acute leukemia (AL) or myelodysplastic syndrome (MDS). EBV was monitored weekly via semi-quantitative PCR . Preemptive rituximab was given based on peak viral loads, rate of rise in viral loads or biopsy proven post-transplant lymphoproliferative disorder (PTLD). Categorical and continuous baseline characteristics of the cohorts were compared using chi-squared and Kruskal-Wallis tests respectively. EBV Treatment was treated as a time-dependent variable and evaluated for its relationship to overall survival (OS) using Cox proportional modelling, adjusted for age and high or very high Disease Risk Index (DRI) and grade III-IV acute GVHD. Survival estimates were performed by Kaplan-Meier product-limit method. Cumulative incidence (CI) of relapse and non-relapse mortality (NRM) were calculated by the Fine-Gray method. Results Of 165 eligible patients, 101 (61%) had an episode of EBV reactivation at a median of 46 days post-transplant (range 10-221 days). 24 received therapy for EBV. Of these, 4 had biopsy-proven PTLD, and 23 received rituximab alone with 1 receiving R-CHOP for PTLD. An undetectable EBV viral load was achieved in 20 out of 24. The baseline characteristics of the subgroups are presented in Table 1. The median survival of the whole cohort was 79 months with an estimated 2-year OS of 60% (95%CI 56-68) and a median follow up of time of 81 months in survivors. The median survival of the EBV Treatment group was 14 months, compared with 121 months and 81.1 months in the EBV No Treatment and No EBV cohorts respectively (Figure 1). Table 2 lists causes of death per group with relapse and complications of poor graft function (PGF) being the leading causes of death in the EBV Treatment group. The incidence of grade III-IV acute GVHD at 100 days was similar between groups as was the incidence of any chronic GVHD at 6 and 12 months. EBV Treatment was significantly associated with poorer OS even when adjusting for age, high/very high DRI and presence of acute GVHD (HR 2.47 CI 1.46-4.17; p=0.0007). The EBV Treatment group had a significantly higher 2 year CI of NRM compared to the EBV Treatment and No EBV groups (38% vs 11% vs 18% p=0.006) but similar incidence of relapse (Figure 2) . Conclusion In this cohort of AL/MDS patients undergoing TCD alloSCT, those who required treatment for EBV reactivation experienced poorer survival due to increased NRM. This increase in NRM may reflect impaired immune reconstitution of which significant EBV reactivation is a manifestation. Further studies to understand the underlying immune defects post alloSCT that predispose patients to significant EBV reactivation and associated complications is warranted to identify immune recovery strategies that may be employed in this poor prognosis group. Disclosures No relevant conflicts of interest to declare.

Pre-Transplant Use of Tyrosine Kinase Inhibitors Increases Risk of Transplant Associated Thrombotic Microangiopathy - a Single Centre Analysis of Incidence, Risk Factors and Outcomes

Introduction Transplant associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication post hematopoietic stem cell transplant (HSCT). Epidemiology, risk factors, prognosis and treatment of TA-TMA are not very clear. While type of transplant, and use of calcineurin inhibitors (CNIs) are established risk factors for TA-TMA, not much is known of other risk factors that affect TA-TMA and its outcome. We retrospectively analysed data of all patients who underwent allogeneic transplant for hematological malignancies at our centre to understand its incidence, possible risk factors and treatment outcomes. Methods All consecutive patients who underwent allogeneic HSCT for AML, ALL and CML from January 2008 to March 2019 were included. Conditioning regimens used were either myeloablative (CyTBI or BuCY) or reduced intensity (fludarabine with either melphalan, treosulfan or cyclophosphamide with or without 2 Gy TBI). Rabbit ATG was used at a dose of 2.5-5 mg/kg for patients who underwent matched unrelated donor (MUD) transplants. GVHD prophylaxis for matched sibling donor (MSD) and MUD transplants included CNIs with methotrexate or mycophenolate mofetil (MMF). Patients who underwent haploidentical (haplo) HSCT received post transplant cyclophosphamide (PTCy) on d+3 and d+4 and CNI with MMF from day+5 onwards. Definitive TA-TMA was defined using Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) criteria ie schistocytes ≥2/HPF, elevated LDH, renal compromise (increase in creatinine 2 times baseline or 50 % decrease in creatinine clearance from baseline ) or unexplained neurological manifestations and negative coombs test. Probable TMA was defined as per criteria proposed by Cho et al ie schistocytes ≥2/HPF, elevated LDH, negative coombs test, no coagulopathy, drop in haemoglobin and thrombocytopenia (platelet < 50 x 109/L or > 50 percent decline in platelet count). Risk factors explored for development of TA-TMA were age, gender, diagnosis, type of transplant, acute and chronic GVHD, use of tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib or sorafenib pre transplant and conditioning regimen used. Factors evaluated to affect the outcomes of TA- TMA were gender, baseline LDH, least platelet count, presence of acute GVHD, TA-TMA index (LDHx1000/platelet count per cumm), definitive vs probable TMA, and type of transplant. All categorical data was compared using Chi-square /Fisher exact test. OS probabilities were calculated using Kaplan -Meier method and were compared using log-rank test. Multivariate analysis to assess risk factors for TMA was carried out using logistic regression. Results Total 241 patients, 179 (74.2 %) male and 62 (25.7 %) female, with median age of 28.5 (3- 53) years were analysed. Donors were MSD (6/6 matched -174, and 9/10 matched-1), MUD (16) or haplo (50) donors. Diagnoses were 104(43 %) - AML, 85 (35%) - ALL (of which Ph+ patients --23) and 52 (22%) -CML patients. Conditioning regimens given were myeloablative (MAC; n= 64, 27 %) or reduced intensity (RIC; n=177, 73 %). Total 26 (10.7%) patients developed TA-TMA; 22 (85%) were males. Table 1 shows clinical features at diagnosis of TA-TMA. Median day of diagnosis of TA-TMA was d+102 (range 12- 722) post HSCT. Analysis of potential risk factors for TA-TMA is shown in table 2. Use of pre-HSCT TKI (OR 2.7, p=0.028), haplo HSCT (OR 3.16, p=0.018) and presence of acute GVHD within 30 days of diagnosis of TA-TMA (OR 4.17, p=0.003) were identified to be significant factors on multivariate analysis. CNIs were omitted as soon as TA-TMA was diagnosed. Low dose defibrotide (5mg/kg BD) was used in 4 patients. No patient received plasma exchange. Median follow up for whole cohort was 59.5 months. Median OS for whole cohort was 59.9 months (figure 1). The OS (figure 2) at 5 years was 51.1% in the patients who did not develop TA-TMA vs 29.6% in the group with TA-TMA (P=0.026).Ten (39%) patients with TA-TMA are alive at the time of analysis. No significant factors affecting outcomes of TA-TMA were identified. Conclusion Incidence of TA-TMA was 10% in our cohort. Pre-transplant TKI use, acute GVHD, and haplo HSCT are independent risk factor for TA-TMA. This is the first study in our knowledge to show pre-transplant TKI as a risk factor for development of TA-TMA. Higher index of suspicion of TA-TMA is thus warranted for those patients who receive pre transplant TKI. Disclosures No relevant conflicts of interest to declare.

Risk Factors for Recurrent CMV Reactivation in CMV Seropositive Recipients Following T Cell Depleted Haematopoietic Stem Cell Transplantation

▪Introduction:Cytomegalovirus (CMV) end-organ disease is a serious complication after allogeneic stem cell transplantation (Allo-SCT). Seropositive status and the use of T cell depleted grafts are major risk factors for CMV reactivation due to delayed immune reconstitution. However, not all recipients of T cell depleted grafts experience CMV reactivation. Indeed some recipients only experience one reactivation episode, while others show persistent or recurrent CMV reactivation.Aim: To identify additional risk factors which contribute towards recurrent CMV reactivation in the first 100 days in CMV seropositive recipients following T cell depleted grafts.Patients and Methods:A retrospective study was performed from January 2004 to February 2014 at University Hospital of Wales, UK. CMV viral load was determined by real time PCR and T cell recovery was determined by flow-cytometry. Non-normal distribution data were expressed as median values (range). Chi-square test was used to compare differences between groups of categorical data. All statistical analyses were performed using SPSS 20 software (Chicago, IL).Results: During the study period a total of 296 patients received allogeneic transplants of whom 124 (42%) were CMV seropositive. Recipient seropositive / donor seropositive (R+/D+) were 53% while 46% were recipient seropositive / donor seronegative (R+/D-). The median age was 56 years (range 19-72) and 64 (51%) were male. All patients received T cell depletion with either Campath-1H (111 patients 90%) or rabbit ATG (13 patients 10%). 32% had a sibling (SIB) donor and 68% a matched unrelated donor (MUD). 21% had no CMV reactivation during the first 100 days, 31.5% had one reactivation episode and 42.5% had a median of 2 episodes (range 2-5). A CD4 count at day + 100 of <50 cell/ul was the most significant risk factor in predicting CMV reactivation p=0.002. We then assessed associated factors that may predict for failure of recovery of CD4 count at day + 100. We found that patients who were refractory to first and/or second line of chemotherapy but subsequently responded to salvage therapy achieving either CR or PR showed significant correlation with recurrent CMV reactivation and low CD4 count at day + 100 following transplant (p=0.031) when compared with those who achieved CR to first line of chemotherapy. Also AML as the underlying disease was associated with both failure of recovery of CD4 count and an increased risk of recurrent CMV reactivation p=0.001 compared with all other disease groups. On the other hand, we didn’t find any significant association with low CD4 count and other factors like recipient age (p=0.489), time from diagnosis to transplant (p=0.203), conditioning regimens (p=0.093), presence of acute GVHD (p=0.410) and concomitant fungal infection (p=0.675).Conclusion: Failure of response to first and/or second line therapy and underlying diagnosis of acute myeloid leukaemia are associated with a lower CD4 count at day + 100 and increased risk of recurrent CMV reactivation in CMV seropositive recipients following T cell depleted graft. DisclosuresNo relevant conflicts of interest to declare.

Impact of Single or Associated CMV, EBV and BK Virus Reactivation Early after Allogeneic Hematopoietic Stem Cell Transplantation on Relapse Incidence

▪Background:Many recent studies have evaluated the impact of cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) showing a significant association with reduced risk of relapse. On the other hand, other frequent viral infections or reactivations like Epstein-Barr virus (EBV) and BK virus (BK-V) have not been evaluated in the same context and we do not know whether their association has an impact on transplantation outcomes or not.Objective:The aim of this study is to evaluate the impact of CMV, EBV and BK-V reactivation up to 3 months after allo-HSCT whether alone or associated on the relapse incidence of patients with hematological malignancies.Patients and methods:We evaluated 359 consecutive patients with hematological malignancies who received allo-HSCT and were followed in our center between January 2008 and June 2013; there were 218 (61%) males and 141 (39%) females with a median age of 48 years (range: 18-70), 182 (51%) had acute myeloid leukemia, 44 (12%) multiple myeloma, 34 (9%) myelodysplastic syndrome, 30 (8%) Non-Hodgkin lymphoma, 7 (2%) chronic lymphocytic leukemia, 21 (6%) myeloproliferative syndrome, 14 (4%) Hodgkin disease, 13 (4%) chronic myeloid leukemia and 14 (4%) aplastic anemia. At transplantation, 227 (63%) patients were in complete response (CR) or chronic phase (CP) and 132 (37%) were in less than CR or CP. For conditioning regimen, 171 (48%) were myeloablative and 188 (52%) were reduced intensity. DNA levels of CMV, EBV and BK-V in blood were detected by quantitative real-time polymerase chain reaction (RQ-PCR) after weekly monitoring up to 3 months after allo-HSCT. CMV-DNA, EBV-DNA or BK-V-DNA was considered positive when the copies exceeded 1000 copies/ml.Results:Among 359 patients, there were 102 patients who had CMV reactivation after a median time of 1.4 months (1.1-1.8) after allo-HSCT with a cumulative incidence of 25 % (24-26) at 3 months; 222 patients had EBV reactivation after a median time of 1.3 months (0.7-2.5) after allo-HSCT with a cumulative incidence of 48 % (47-50) at 3 months; and 38 patients had BK-V reactivation after a median time of 1.1 months (0.7-1.5) after allo-HSCT with a cumulative incidence of 10 % (9-11) at 3 months. The cumulative incidence of relapse at one and two years for the whole population was 27% (26-28) and 34% (33-35) respectively and the cumulative incidence of transplant-related mortality (TRM) was 22% (21-23) and 25% (24-26) respectively. The multivariate analysis took into account the type of disease, the type of conditioning, the disease status at transplantation, the presence of acute GVHD and single or the association of viral reactivation; this analysis showed that the presence of a single viral reactivation was associated with a significant lower relapse rate, for CMV: sdHR=0.34 [0.12-0.92], p=0.03, for EBV: sdHR= 0.52 [0.35-1], p=0.05 and for BK-V: sdHR=0.58[0.24-0.7], p=0.002; and that patients who have an associated CMV and EBV reactivation had significantly higher risk of relapse, sdHR= 5 [1.59-16], p=0.006. There was no significant impact of these reactivations on TRM.Conclusion:We confirmed the positive impact of CMV reactivation on relapse incidence, in addition we demonstrated that this impact exists also for EBV and BK-V, however we showed for the first time that the association of CMV and EBV was significantly associated with a higher risk of relapse. More investigations are ongoing to evaluate the immunological status of these patients and the different administered anti-viral treatments. DisclosuresNo relevant conflicts of interest to declare.

The oral iron chelator deferasirox might improve survival in allogeneic hematopoietic cell transplant (alloHSCT) recipients with transfusional iron overload

IntroductionIron overload (IO) has been shown to be an important cause of mortality and morbidity in patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). This study aimed to evaluate the possible effect of oral iron-chelation treatment (deferasirox) on survival in alloHSCT recipients in the posttransplant period. Materials and methodsA total of 80 alloHSCT recipients with IO were analyzed, retrospectively. Pretransplant and posttransplant data were obtained from the patients’ files. Patients were divided into two groups. Group 1; patients who did not receive any chelator treatment due to side effects or compliance problems. These patients were treated by phlebotomy. Group 2 consisted of patients who received deferasirox treatment. ResultsThe median treatment duration with deferasirox was 122days (min–max:91–225). The iron chelating treatment significantly reduced serum ferritin levels administered at a dosage of 20–30mg/kg/day (p<0.001). The median OS in Group 1 was found 16.0 (min–max:1.0–63.0) months and 25.0 (min–max:3.0–72.0) months in Group 2. In univariate and multivariate analysis, patients in Group 1 showed poorer OS compared to those in Group 2 with an increase in risk of death (HR:3.22, min–max:1.67–6.23, p=0.001 and HR:3.51,, min–max:1.75–6.99, p<0.001; respectively). The median DFS in Group 1 was found 11.0 (min–max:3.0–24.0) months and 22.0 (min–max:8.0–43.0) months in Group 2. The difference was found statistically significant (p=0.023). The other factors that we found significant difference in multivariate analysis between groups were; presence of acute GVHD (patients with aGVHD had increased risk of death compared to patients without aGVHD (HR:2.49, min–max: 1.32–4.69, p=0.005), chronic GVHD (HR:2.57, min–max:1.23–5.41, p=0.013), median interval to tx (HR: 2.23, min–max:1.17–4.26, p=0.015) and HLA match (HR:3.01, min–max:1.35–6.73, p=0.007) ConclusionOral deferasirox (Exjade) treatment may improve survival in patients with iron overload who underwent alloHSCT.

IMPACT OF PRETRANSPLANT DONOR AND RECIPIENT CYTOMEGALOVIRUS SEROSTATUS ON OUTCOME FOR MULTIPLE MYELOMA PATIENTS UNDERGOING REDUCED INTENSITY CONDITIONING ALLOGENEIC STEM CELL TRANSPLANTATION.

Scope of the study was to investigate the impact of pre-transplant CMV serostatus of the donor and/or recipient on the outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-SCT) for Multiple Myeloma (MM). To our knowledge no data are available in the literature about this issue.We retrospectively followed 99 consecutive patients who underwent reduced-intensity conditioning (RIC) Allo-SCT for MM in our cancer center at Marseille between January 2000 and January 2012. Based upon CMV serostatus, patients were classified as low risk (donor [D]−/recipient [R] −) 17 patients (17.1%), intermediate risk (D+/R) 14 patients (14.1%), or high risk – either (D−/R+) 31 patients (31.3%) or (D+/R+), 37 patients (37.3%).Cumulative incidence of CMV reactivation was 39% with a median time of 61 days (26–318). Three patients (3%) developed CMV disease. Two factors were associated with CMV reactivation: CMV serostatus group (low: 0% vs. intermediate: 29% vs. high: 50%; p=0.001) and the presence of grade II–IV acute GvHD (Hazard Ratio: HR=2.1 [1.1–3.9]). Thirty-six of the 39 patients (92%) with CMV reactivation did not present positive detection of CMV after a 21-day median duration preemptive treatment with ganciclovir. Cumulative incidence of day 100 grade II–IV acute GvHD, 1-year chronic GvHD and day 100 transplantation related mortality (TRM) were 37%, 36% and 9%, respectively. CMV reactivation and serostatus were not associated with increased GvHD and TRM or short survival. Only the presence of acute GvHD as a time dependent variable was significantly associated with increased TRM (p=0.005). Two-year overall and progression free survival were 56% and 34%, respectively.Donor and recipient CMV serostatus and acute GvHD are independent factors for increased CMV reactivation in high-risk MM patients undergoing RIC Allo-SCT. However, we did not find any influence of CMV reactivation on post transplantation outcome. CMV monitoring and pre-emptive treatment strategy could in part explain these results. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this group of patients, warranting further prospective studies.

Allogenic Transplantation in Lymphomas: A Focused Analysis On Aggressive Lymphomas and Factors Predictive of Outcome in a Series of 179 Pts Treated At John Theurer Cancer Center.

AbstractAbstract 3120▪▪This icon denotes a clinically relevant abstract Introduction:Chemo-immunotherapy (i.e. rituximab combinations) has clearly had a significant impact on the outcome of all B-cell NHL both in terms of PFS and OS. However in the relapse/refractory setting a large proportion of pts still do very poorly especially in aggressive subtypes including DLBCL and MCL. Salvage therapy followed by HDT-ASCT in relapsed DLBCL remains the standard, though pts with early failures (<1y) and/or prior exposure to rituximab still show dismal results (CORAL data). In MCL the use of HDT-ASCT in the relapse setting is debated given the frequency of chemo-resistance leading to poor results even in second CR. The use of allogeneic transplantation was developed based on observations c/w with a clear GVL effect in NHL as illustrated by pts going into remission after DLI injections. The development of non-myeloablative approaches has allowed expansion of use of allogeneic BMT in relapsed/refractory NHL. We report here one of the largest series (179 consecutive pts) with relapsed/refractory lymphoma focusing on overall survival and outcome predictors. Methods:Utilizing Kaplan-Meier survival and Cox regression methods, we report on the outcome of 179 consecutive pts with relapsed/refractory lymphoma who underwent allogeneic stem cell transplantation at the John Theurer Cancer Center between 1995–2012. The primary study endpoint was overall survival (OS) assessed by chart and SSDI database review. Secondary study endpoints included examination of the association between overall survival and allogeneic stem cell source, donor source, development of GVHD, pre-transplant chemo-sensitivity and prior failure to HDT-ASCT (second transplant). The proportional hazards assumption was met for this analysis. Results:Survival data on 179 pts (median age 48, range 20–71) were analyzed, representing 86 deaths and 5720 total months at risk (median follow up=12.3 months). Baseline characteristics included: ECOG PS (med 1, range 0–2), diagnosis (25% DLBCL, 21% HD, 20% MCL, 13% FCL, 13% PTCL, 8% other), donor source (50% matched SIB, 31% MUD, 19% mismatched MUD), stem cell source (73% PB, 23% BM, 6% Cord) and prior autologous SCT (38%). The median OS for the entire cohort was 31.2 months. OS KM curves by selected aggressive NHL subtypes are represented in Figure 1. We performed COX regression analyses to address outlined secondary endpoints. In univariate analyses statistically significant inferior outcomes were associated with the use of mismatched unrelated donor (HR 1.4, p=.01, Figure 2), bone marrow donor stem cells vs. PBSCT (HR=1.7 p=.04), pre-transplant stable/refractory disease (HR 1.8, p=.03), absence of cGVHD (HR=4.7, p<.001) and presence of acute GVHD (HR 2.8, p=.001). No difference in OS was detected whether pts had undergone allogeneic SCT as a second transplant (med time between auto/allo=20.9 months) following relapse after auto SCT (HR 1.14, CI .75–1.73, p=.5). Conclusions:This series represents a large cohort of poor risk, relapsed/refractory lymphoma pts treated consecutively with allogeneic stem cell transplantation over a > 10-year period at our institution with the following observations: 1.These data clearly demonstrate that a sizable subset of pts with either HL or aggressive NHL (MCL, DLBCL, PTCL) can enjoy long disease-free survival following allo SCT (beyond the expectation of standard salvage chemotherapy).2.Relapse following autologous SCT should not preclude consideration of allo SCT as second salvage.3.New strategies to improve outcome include our ongoing TH2 study which led to reduced GVH incidence and promising outcome.4.Our ongoing study looking at expanded donor derived T-cells is showing promising results in reducing GVH incidence and improving outcome, including in aggressive NHL, and will be presented on a separate presentation. [Display omitted] [Display omitted] Disclosures:Mato:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau. Goldberg:Eisai: Speakers Bureau. Feldman:Allos: Speakers Bureau; celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau; Merck: Speakers Bureau. Goy:Milennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; J & J: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees.

Impact of Pretransplant Donor and Recipient Cytomegalovirus Serostatus On Outcome for Multiple Myeloma Patients Undergoing Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

AbstractAbstract 4496 Purpose:To investigate the impact of pre-transplant CMV serostatus of donor or recipient on outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-SCT) for Multiple Myeloma (MM). Patients and methods:We retrospectively followed 99 consecutive patients who underwent reduced-intensity conditioning (RIC) Allo-SCT for MM in our cancer centre at Marseille between January 2000 and January 2012. Based upon CMV serostatus, patients were classified as low risk (donor [D]-/recipient [R]-) 17 patients (17.1%), intermediate risk (D+/R) 14 patients (14.1%), or high risk – either (D-/R+) 31 patients (31.3%) or (D+/R+), 37 patients (37.3%). Results:Cumulative incidence of CMV reactivation was 39% with a median time of 61 days (26–318). Three patients (3%) developed CMV disease. Two factors were associated with CMV reactivation: CMV serostatus group (low: 0% vs intermediate: 29% vs high: 50%; p=0.001) and the presence of grade II–IV acute GvHD (Hazard Ratio: HR=2.1 [1.1–3.9]). Thirty-six of the 39 patients (92%) with CMV reactivation did not present positive detection of CMV after a 21-day median duration preemptive treatment with ganciclovir. Cumulative incidence of day 100 grade II–IV acute GvHD, 1-year chronic GvHD and day 100 transplantation related mortality (TRM) were 37%, 36% and 9%, respectively. CMV reactivation and serostatus were not associated with increased GvHD and TRM or short survival. Only the presence of acute GvHD as a time dependent variable was significantly associated with increased TRM (p=0.005). Two-year overall and progression free survival were 56% and 34%, respectively. Conclusion:Donor and recipient CMV serostatus and acute GvHD are independent factors for increased CMV reactivation in high-risk MM patients undergoing RIC Allo-SCT. However, we did not find any influence of CMV reactivation on post transplantation outcome. CMV monitoring and pre-emptive treatment strategy could in part explain these results. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this specific group of patients, warranting further prospective studies.Table 1Patient and transplantation characteristicsPatient and transplantation characteristicsn = 99 (%)Patients Age (median) [range]53 years [27–67]Male gender59 (60)Myeloma-subtypeIgG52 (53)IgA23 (23)Light Chain12 (12)Bence jones8 (8)Other4 (4)Cytogenetics at diagnosisNormal14 (14)Del(13) or Del (17) or t(4;14)24 (24)NA61 (62)Median number of prior chemotherapies before Allo-SCT [range]2 [1–5]1 line27 (27)2 lines46 (47)3 lines15 (15)>3 lines11 (11)Median number of prior Auto-SCT [range]2 [1–4]157 (58)231 (31)> 28 (8)Status of Myeloma at Allo-SCTCR12 (12)VGPR10 (10)PR/SD66 (67)PD11 (11)Median interval between Auto- and Allo-SCT months [range]19 [1–89]Donor typeMRD73 (74)URD26 (26)Donor/recipient sex mismatch48 (48)ABO compatibilityYes63 (64)No36 (36)Donor/recipient CMV serostatusD−/R− (low risk)17 (17)D+/R− (intermediate risk)14 (14)D+/R+ (high risk)31 (31)D−/R+ (high risk)37 (37)Donor Median age years (range)46 (20–71)Conditioning regimenFlu + Bu + ATG68 (69)Flu + TBI25 (25)Other RIC6 (6)GvHD prophylaxisCSA56 (57)CSA+MMF41 (41)MMF2 (2)Stem cell sourcePeripheral Blood88 (89)Bone Marrow9 (9)Cord blood2 (2)Stem cell dose median [range]CD34+ × 106/kg5.41 [0.16–12.8]CD3+ × 106/kg299 [5–745] Legend:CR, complete remission; VGPR, very good partial remission; PR, partial remission, PD, progressive disease; Flu, fludarabine; Bu, busulfan; ATG, antithymocyte globulin; CR, complete remission; VGPR, very good partial remission; PR, partial remission, PD, progressive disease; MRD, matched related donor; URD, unrelated donor; GVHD, graft versus host disease; CSA, cyclosporine A; MMF, mycophenolate mofetyl.Table 2CMV reactivationCumulative incidence of CMV reactivationpAll patients (n=99)39%CMV serostatusLow risk (n=17)0%0.001Intermediate risk (n=14)29%High risk (n=68)50%Donor type*MRD (n=72)38%0.427URD (n=24)46%Graft source*PBSC (n=88)38%0.215Bone marrow (n=8)63%Transplantation period<2006 (n=42)33%0.368>=2006 (n=57)43%Conditioning regimen with ATGYes (n=68)43%0.164No (n=31)29%CMV detection methodpp65 (n=65)38%0.819PCR (n=34)39%Acute GVHD$HR=2.1 [1.1–3.9]0.032Chronic GVHD$HR=0.8 [0.1–8.6]0.837$The occurrence of GVHD was analysed as a time dependent variable Disclosures:No relevant conflicts of interest to declare.

OUTCOMES In SEVERE Aplastic Anemia Treated with RELATED Allogeneic STEM CELL TRANSPLANTATION (BM/PBSC): 14 YEARS of FOLLOW up In Peru

Abstract 4530 BACKGROUNDThe treatment of acquired SAA is based on allogeneic stem cell transplantation (SCT) and immunosuppressive therapy. Up to 68% of patients in our country are treated without transplantation, and in our hospital a preliminary report (1999–2006) shows that 56% of these patients have achieved partial or complete response. Peruvian patients with aplastic anemia usually present poor prognosis factors, such as more than 6 months of diagnosed disease before transplantation (53%) and more than 15 RBC transfusions before the procedure (69%). The aim of this study was to assess the outcome of children and adults with SAA, treated with related allo-transplant and the evolution of patients with poor prognosis factors in Hospital Rebagliati (Lima, Peru - 1995 to 2010). DESIGN AND METHODSRetrospective and Descriptive analysis where was included variables related to the patients, disease and method of transplantation in 88 patients of the 95 who went to transplant. RESULTSThe median age at diagnosis was 26 years (3–55 years), male/female ratio: 1.75, the interval between diagnosis – SCT was 12.7 months (1–151 months), in 47.7% of patients this interval was ≤ 6 months. GVHD prophylaxis consisted of CsA + MTX. The conditioning regimen was ALG equine or rabbit (based on availability), + cyclophosphamide in 95% of patients and cyclophosphamide + busulphan in 1%; 59 patients received equine anti-lymphocyte globulin and 27 patients received rabbit anti-lymphocyte globulin. The stem cell source was bone marrow in 35.2% (31), peripheral blood in 58% (51), bone marrow and peripheral blood in 5.7% (5) and umbilical cord blood 1.1% (1). Two of the 88 patients required a second transplant and continue alive.The stem cell source did not show a significant difference in the time to neutrophil engraftment (p=0.15), which took place around day 13 (10–28 days). The dose of MNC used was 3×108/kg when BM was the graft source and CD34 > 2×106 if the source was peripheral blood. The engraftment was done all patients (n:88).The mortality rate was 19.4% after BMT, despite the number of RBC transfusions and mostly due to lost of engraftment, and 9.8% after using peripheral blood as the graft source.The overall survival was 80.5%, this patients were followed for a period up to 157 months. There was not a significant difference in survival with the use of bone marrow or peripheral blood as the stem cell source (p=0.2); nonetheless, we observed a trend toward better survival rates when performing PBSCT, according to the time interval between diagnosis to SCT and the number of transfusions.The kind of anti-lymphocyte globulin –horse or rabbit origin- used, did not show a major impact in survival (p=0.13). A major predictor of a significantly improved HSCT outcome in Peru, was the development of acute GVHD (p=0.03). CONCLUSIONSOS is 80%, superior compared with immunosuppressive therapy alone (56%). The presence of acute GVHD is a major predictor of survival in those receiving SCT. The use of peripheral blood as the stem cell source seems to improve survival in Peruvian patients with poor prognosis factors, in comparison with the use of bone marrow source. Disclosures:No relevant conflicts of interest to declare. [Display omitted] [Display omitted]

Prognostic Factors of Reducing Relapse in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation From Related Donor for Acute Myeloid Leukemia: The Japan Society for Hematopoietic Cell Transplantation (JSHCT) AML Working Group

Abstract 3085 Background:A llogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute myeloid leukemia (AML), however a major obstacle to success is represented by the relapse of the disease. We retrospectively analyzed prognostic factors to determine whether there are clinical features that predict relapse after transplantation. Patients and Methods:Clinical data were collected from the Transplant Registry Unified Management Program (TRUMP) in Japan. An individual patient data-based analysis was performed on patients with AML who achieved or continued complete remission (CR) after related allo-HCT between 1991 and 2009. A logistic regression model was used to analyze associations between relapse and clinical factors. Patients with CR1 or CR2 were defined as having a standard-risk disease, and patients with ≤CR3 or non-CR were defined as having a high-risk disease. Conditioning regimens included ≤ 8Gy in fractionated doses of total body irradiation, busulfan dose < 9mg/kg, melphalan dose ≤ 140 mg/m2 defined as a reduced-intensity conditioning (RIC) regimen. Results:We analyzed a cohort of 1, 960 patients with AML. The median age at allo-HCT was 42 years (range, 16 to 74 years). Among the 1, 960 patients, 778 patients (38%) relapsed after allo-HCT. The probabilities of survival at 5-year for all patients, standard-risk patients, and high-risk patients were 49%, 61%, and 31%, respectively. In a multivariate analysis, significant factors for no relapse were standard-risk disease at the time of allo-HCT (HR 0.366, 95%CI 0.279–0.480, p<0.0001), presence of chronic GVHD (HR 0.442, 95%CI 0.338–0.579, p <0.0001), and CMV infection (HR 0.452, 95%CI 0.230–0.886, p =0.021). Intensity of conditioning regimen (RIC vs myeloablative), disease subtype of AML, HLA matching (matched donor vs mismatched donor), source of stem cells (peripheral blood vs bone marrow), and presence of acute GVHD did not affect relapse rates. Conclusion:These results indicate that in patients with standard-risk AML at the time of HCT, chronic GVHD or CMV infection after HCT were crucial for reducing relapse. Immune modulation mediated by chronic GVHD or CMV infection may have played a role in preventing disease relapse. The use of donor lymphocyte infusion before relapse may reduce the recurrence for selected patients who do not develop chronic GVHD. Disclosures:No relevant conflicts of interest to declare.

Changing to a New Donor for Second Hematopoietic Stem Cell Transplantation in Fanconi Anemia Seems to Improve Survival.

Abstract 2294Poster Board II-271This retrospective analysis of the EBMT ProMISe database was designed to investigate the role of donor choice for second hematopoietic stem cell transplantation (HSCT) in Fanconi Anemia (FA). Our hypothesis was that using a different donor for the second HSCT would increase the probability of survival, the patient not being sensitized to donor antigens as a result of the first HSCT. We conducted a survey of the EBMT ProMISe database in order to identify FA patients transplanted more than once for bone marrow failure and retrospectively analyzed their data to determine overall survival and presence of acute GvHD. A donor for the second HSCT was defined as the “same” as for the first if both donors had identical: birth date, relation to patient (identical sibling or not), gender and family relation or donor number. A donor was “different” when this information indicated that a different person donated for second HSCT. One hundred and three patients were eligible for the study by the following criteria: diagnosis of Fanconi Anemia (confirmed by chromosome breakage test), presentation with aplastic anemia (AA) and having undergone two HSCTs between August, 1980 and December, 2007. FA patients with myelodysplasia or acute leukemia were excluded. After retracing data in the database, additional questionnaires were sent out to 44 EBMT centers that had performed second HSCTs for FA-AA, asking for supplementary data. In 80 cases (study population), enough information was collected to identify first and second donors. Forty four subjects (25 males and 19 females) received a second HSCT from the “same donor” (SD) and 36 patients (15 males and 21 females) from a “different donor” (DD). The mean age of the study population at second HSCT was 10.7 years (range, 1.8-34.5). Median interval between first and second HSCT was 63 days.At first HSCT patient gender, age at HSCT, use of cyclophosphamide and irradiation in the conditioning regimen and type of rejection were not differently distributed in the SD and DD group whereas significantly more HLA identical sibling donors were used in the SD (31%) vs. DD (11%) group (p=0.027). In 68.2% of the SD group bone marrow was used vs. in 52.7% of the DD group (p=0.002). Median cell dose in SD group was 9×106 CD34+/kg and in DD group 1.8×106 CD 34+/kg (p=0.002). At second HSCT age at HSCT, use of cyclophosphamide and irradiation in the conditioning regimen, dose of CD34+ cells and cell source were not differently distributed between SD and DD groups whereas significantly more HLA identical sibling donors were used in SD (31%) vs. DD (11%) group (p=0.027).Overall survival of all 80 patients at one year from second transplant is 36%. Probability of overall survival after 7 years is 35%. An interval between first and second HSCT of >80 days resulted in better survival (p=0.007). Overall survival at 7 years is 41% in DD and 26% in SD patients (Cox regression, HR 0.483, p=0.017). This difference remained significant after correction for the confounding effects of irradiation in first HSCT and relation donor/patient (identical sibling or not). Rejection rate after second HSCT was similar in SD and DD group (54.5%). Death occurred in 73% of SD vs. 56% of DD. Causes of death included infections (70% in SD vs. 48% in DD) and rejection (39% in SD and 38% in DD). Noteworthy more than one major cause of death was often found in the same patient. Only 2 secondary tumors were reported in the whole group. Acute GvHD gr II-IV was not significantly different in SD vs DD groups (multivariate logistic regression models, OR 1.642, p=0.47).Our data suggest that after having failed a first transplant, using the same or a different donor does not affect the occurrence of aGVHD, whereas change of donor would improve the survival of FA patients in need of a second HSCT for AA. Mechanisms underlying rejection of a first HSCT should be studied more in depth. International centers should collaborate in finding the most appropriate regimen for first and second transplants in FA. Disclosures:No relevant conflicts of interest to declare.

Clinical Significance of Autoantibody Expression in Allogeneic Stem Cell Recipients.

Some allogeneic stem cell recipients manifest autoimmune disease-like symptoms associated with the occurrence of various autoantibodies. We studied the association of autoantibodies with chronic graft-versus-host disease (cGVHD) and survival in allogeneic stem cell recipients. From Nov. 2001 to Mar. 2008, 121 patients with hematological diseases who had survived at least 3 months after allogeneic stem cell transplantation (SCT) were enrolled in the current study. Forty-seven patients (38.8%) expressed at least one of various autoantibodies after allogeneic SCT. ANA was expressed most commonly in recipients (n=22, 18.2%). Anti-dsDNA antibody was positive in 7 (5.8%), anti-Sm antibody in 6 (5%), rheumatoid factor (RF) in 17 (14.0%), and positive Coombs test in 12 (9.9%). The FANA pattern revealed 11 nucleolar, 6 speckled, and others (n=5). Positive rate of autoantibody was higher in patients with cGVHD (47.8 vs. 27.8%; p=0.025) and in patients with extensive cGVHD (62.5 vs. 27.2%; p<0.001). The expression of autoantibodies had a statistical correlation to specific organ involvement of cGVHD: ANA to sicca syndrome (p=0.010), anti-Sm antibody to hepatic GVHD (p=0.003), and RF to sicca syndrome (p=0.039) and musculoskeletal GVHD (p=0.026). The 5-year survival of autoantibody-positive patients was 63.8% and that of negative patients was 47.9% (p=0.003). The incidence of underlying disease relapse was lower in autoantibody-positive patients (20.2% vs. 39.3%; p=0.011). However, GVHD-specific survival was not related with autoantibody expression. Advanced age group (p=0.005, OR=0.246), unrelated donor (p=0.005, OR=0.218), and the presence of acute GVHD (p=0.029, OR=0.315) were significantly associated with a lower incidence of autoantibody expression. In conclusion, the expression of autoantibodies after allogeneic SCT was related with cGVHD. Patients expressing autoantibodies had a better survival and low incidence of underlying disease relapse.

T Cell Reconstitution in First 200 Days Post Transplantation Predicts Long Term Survival in Allogeneic Hematopoetic Progenitor Cell Transplantation (HPCT).

Background: Successful reconstitution of cellular immunity following allogeneic HPCT reduces the risk of relapse and confers protection against opportunistic infections. We performed an IRB-approved retrospective analysis of patients who underwent allogeneic HPCT and in whom the content of immune cells were measured in the graft and in post-transplant blood samples.Methods: The study population consisted of 122 patients with hematologic disorders (71 acute leukemia; 14 chronic leukemia; 18 lymphoma, 12 MDS; 3 aplastic anemia; and 4 other) who underwent HPCT with a non-T cell depleted graft from an HLA matched related (73) or unrelated (49) donor. 47 patients had low risk disease (AA, ALL CR1, AML CR1, CML CP1), while 75 had high risk disease (all others). The conditioning regimen was non-myeloablative in 38 (31%), included ATG in 18 (15%), and included TBI in 54 (44%). Peripheral blood was drawn at a median of 101 days post-HPCT and analyzed for T-cell subsets, B-cells, NK cells, and dendritic cells. Subjects were divided into three strata based upon the maximal value for the content of each cell subset in the blood. Univariate and multi-variable stepwise logistic regression analyses were performed to test the association of pre-transplant clinical factors, the cells in the graft, and the numbers of immune cells in the blood post-transplant with overall survival.Results: The estimated three-year survival for all subjects was 53%, with death in 49/122 patients (40%) due to progressive disease (37%), infection (29%), GVHD (20%), and other causes (14%). Univariate factors associated with death included high risk, age, the use of reduced intensity conditioning regimen, the use of TBI, the use of ATG during conditioning and the measurement of lower numbers of total T-cells, CD4+ T-cells, CD8+ T-cells, γδ T-cells, DC1 and DC2 in the peripheral blood during the first 200 days post-transplant. A multi-variable Cox model identified non-myeloablative conditioning (HR 2.2, 95% CI 1.2–3.9), TBI (HR 1.9, 95% CI 1.1–3.3), transplant risk strata (HR 1.9, 95% CI 1.0–3.6), and a blood CD3+ T-cell count of less than 600 cells/mcL (HR 1.8, 95% CI 1.2–2.5) as independent risk factors for post-transplant death. The presence of acute GVHD (all grades) or graft constituents was not significantly associated with survival. Limiting the study population to those subjects who survived at least 100 days showed that blood CD3+ T-cells, non-myeloablative conditioning, the use of TBI remained significantly associated with survival.Conclusions: Higher CD3+ counts in the early post-transplant period predict better survival. Patients who fail to achieve a blood CD3+ T-cell count of >600/mcL in the first 200 days post-transplant may be appropriate subjects for adoptive cellular immunotherapy. [Display omitted] [Display omitted]

The Incidence and Risk Factors of the Euthyroid Sick Syndrome Soon after Allogeneic Hematopoietic Stem Cell Transplantation in Children.

Purpose: In this study, we analyzed the short term change of thyroid function, incidence and risk factors of thyroid dysfunction soon after allogeneic hematopoietic stem cell transplantation(HSCT) in children.Method: We enrolled 80 pediatric patients following allogeneic HSCT, at the Catholic HSCT center between January, 2004 and February, 2006. Serum TSH(thyroid stimulating hormone), total serum thyroxine, total serum triiodothyronine levels were systematically measured in 80 patients before and 1 month, 6 month and 12 month after HSCT.Results: Thyroid function was statistically decreased at 1 month after HSCT(P < 0.001). Thyroid dysfunction at 1 month was observed in 43(54%) of 80 patients, 31(39%) of whom presented with euthyroid sick syndrome. Thyroid dysfunction was normalized within 1 year after HSCT(Table).In univariate analysis, malignant disease and presence of acute GvHD(grade ≥II) were risk factors for euthyroid sick syndrome(P = 0.04, 0.01). In multivariate analysis, we could not detect an independent risk factor for euthyroid sick syndrome(P = 0.19, 0.06).Conclusion: The present study suggests that the incidence of thyroid dysfunction is high after allogeneic HSCT. Therefore, regular monitoring of thyroid hormone levels after HSCT is required.Short-term changes in thyroid function after HSCTPre HSCTPost HSCT 1 monthPost HSCT 6 monthPost HSCT 12 monthT3 (ng/dL)161 ± 27100 ± 35123 ± 35124 ± 35T4 (μg/dL)8.7 ± 1.66.5 ± 2.47.3 ± 1.87.7 ± 1.6TSH (mIU/L)2.9 ± 1.91.2 ± 1.32.4 ± 1.82.1 ± 1.3

Treatment of Enlarged Lymph Nodes in Children and Adolescents

Purpose:Cytomegalovirus(CMV) infection still remains as a major cause of morbidity and mortality after stem cell transplantation. In this study, we analyzed the results of antigenemia-guided pre- emptive therapy among children with allogeneic hematopoietic stem cell transplantation to determine the incidence and risk factors associated with CMV antigenemia, and evaluated the efficacy of the CMV antigenemia based preemptive therapy. Methods:We enrolled 213 pediatric patients following allogeneic hematopoietic stem cell transplantation(HSCT), at the Catholic HSCT center between October 1998 and December 2003. Pre-emptive ganciclovir was started when more than 5 CMV Ag-positive cells were detected in matched sibling HSCT, and when any Ag-positive cells were seen in unrelated allogenic HSCT. Results:CMV antigenemia was observed in 88(41.3 percent) of 213 patients on median day 28(day 11-99). In univariated analysis, use of unrelated donors(other than siblings), age of recipient(more than 5 years at transplant) at transplantation, the presence of recipient CMV-IgG before transplantation, TBI-based conditioning regimen and the presence of acute GvHD(grade ≥II) were the risk factors for positive CMV antigenemia. In multivariate analysis, unrelated bone marrow transplantation, positive recipient CMV serology and acute GvHD(grade ≥II) were the independent risk factors for positive CMV antigenemia. Conclusion:Risk factors of CMV infection in children were CMV serostatus of the recipient, the source of stem cells, and acute graft-versus-host disease. The pre-emptive therapy based on CMV antigenemia was effective in the prevention of CMV disease.