Presence Of Acute Graft-versus-host Disease Research Articles

Profiles of interferon-gamma and interleukin-2 in patients after allogeneic hematopoietic stem cell transplantation.

BACKGROUNDAllogeneic hematopoietic stem cell transplantation (allo-HSCT) may be related to the occurrence of complications, including graft-versus-host disease (GvHD) and infections. The pathogenesis of acute GvHD is connected with T lymphocytes, which identify alloantigens on host's antigen-presenting cells, activate production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), and act on the immune effector cells and damage tissues and organs.AIMThe aim of the study was to investigate and distinguish serum concentration profiles of IFN-gamma and IL-2 within a 30-d period after allo-HSCT.METHODSWe enrolled 62 patients, i.e., 30 (48%) male and 32 (52%) female subjects [median age 49.5 (19-68) years], after allo-HSCT from siblings (n = 12) or unrelated donors (n = 50) due to acute myeloid leukemia with myeloablative conditioning (n = 26; 42%) and with non-myeloablative conditioning (n = 36; 58%). All patients were given standard immunosuppressive therapy with cyclosporin-A and methotrexate and pre-transplant antithymocyte globulin in the unrelated setting. Blood samples were collected pre-transplant before and after (on day -1) the conditioning therapy and on days +2,+4, +6, +10, +20, and +30 after allo-HSCT. Serum levels of IL-2 and IFN-gamma were determined using ELISA. RESULTSPatients were divided into four groups depending on the presence of acute GvHD and clinical manifestations of infection. Group I included patients with neither acute GvHD nor infections [n = 15 (24%)], group II consisted of patients with infections without acute GvHD [n = 17 (27%)], group III was comprised of patients with acute GvHD without infections [n = 9 (15%)], and group IV included patients with both acute GvHD and infections [n = 21 (34%)]. IFN-gamma concentrations were higher in Group II than in other groups on days +20 (P = 0.014) and +30 (P = 0.008). Post-hoc tests showed lower concentrations of IFN-gamma on day +30 in groups I (P = 0.039) and IV (P = 0.017) compared to group II. The levels of IL-2 were mostly undetectable.CONCLUSIONSerum levels of IFN-gamma following allo-HSCT progressively escalate. High serum levels of IFN-gamma are related to infectious complications rather than acute GvHD. Serum concentrations of IL-2 in most patients are undetectable.

Role of therapeutic drug monitoring of intravenous Busulfan for prevention of sinusoidal obstructive syndrome in children.

Therapeutic drug monitoring (TDM) of intravenous busulfan (Bu) has been recommended for safe engraftment and decreased toxicity in children undergoing hematopoietic stem cell transplantation (HSCT). This study aims to compare HSCT-related outcomes, such as acute or chronic graft-versus-host disease (GvHD), sinusoidal obstructive syndrome (SOS), event-free survival (EFS), and overall survival (OS) in children with and without TDM for busulfan. This retrospective study conducted between February 2012 and February 2021 at our Bone Marrow Transplantation Unit included 172 patients (34% girls) with a median age of 4.70years (IQR 2.41-10.01). Group A consisted of 46 patients whose Bu doses were adjusted according to actual body weight, and group B consisted of 126 patients whose Bu dose adjustments made according to TDM. Totally, 32 patients (19%) developed moderate or severe SOS. The incidence of SOS was significantly higher in the group without TDM (29% vs. 15%, p=.041). A multivariable analysis showed that the presence of acute GvHD and one alkylating drug-containing conditioning regimen compared with two or three were associated with SOS (p=.03 and p=.002, respectively). In patients with TDM, cumulative Bu dose and area under curve also were not associated with SOS. Other HSCT-related outcomes such as acute or chronic GvHD, relapse and graft rejection rates, OS and EFS rates did not differ between the groups. TDM and making dose adjustments with Bayesian forecasting over four days of Bu therapy optimizes exposure and reduces the risk of SOS in children undergoing HSCT.

Room for Improvement: A 20-Year Single Center Experience with Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes

Allogeneic stem cell transplantation (allo-SCT) remains the only curative therapeutic approach for patients with myelodysplastic syndromes (MDS). The aim of the study was to assess the efficacy/safety of allo-SCT as well as to identify factors influencing post-transplant survival. One hundred and two MDS patients (median age: 48 years; 57 males) who underwent allo-SCT were retrospectively evaluated. Twenty seven patients were transplanted from HLA-matched sibling and 75 patients received grafts from unrelated donors. Peripheral blood was a source of stem cell for 79 patients. Reduced intensity conditioning was used in 64 subjects. Acute and chronic graft versus host disease (GvHD) developed in 61 and 19 of patients, respectively. In total, 61 patients have died. The causes of deaths included infectious complications (n = 30), steroid-resistant GvHD (n = 17), MDS relapse (n = 9) and transformation to AML (n = 5). Non-relapse mortality and cumulative incidence of relapse at 2 years were 49.8% and 9%, respectively. 41 patients are alive at last contact and present full donor chimerism. 38 patients remain in complete hematological remission (CHR), 3 patients had CHR with incomplete platelet recovery. Median follow-up from diagnosis of MDS and transplantation are 27.1 months and 7 months respectively. Overall survival and relapse-free survival were 41% at 2 years. Increased serum ferritin level > 1000 ng/ml, presence of acute GvHD, grades III–IV acute GvHD and high hematopoietic cell transplantation-comorbidity index were found to negatively influenced survival. Allo-SCT for MDS is feasible procedure with a proportion of patients to be cured.

Haploidentical transplantation is feasible and associated with reasonable outcomes despite major infective complications–A single center experience from India

Haploidentical stem cell transplantation (SCT) using post-transplantation cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis is a reasonable therapeutic option for patients who do not have a matched sibling donor. Between 2010 and June 2020, 257 patients underwent 269 Haploidentical transplantations, including 122 children. Indications included both malignant (56.8%) and non-malignant (43.2%) diseases. Conditioning regimens included both myeloablative (57.6%) and nonmyeloablative regimens (42.4%). Peripheral blood stem cells were the predominant graft source (96.2%). Based on the disease risk index, patients were classified into early-, intermediate-, and late-stage disease. Engraftment was seen in 205 patients (76.2%) whereas 39 (14.4%) died before engraftment and 23 (8.6%) had primary graft failure. The cumulative incidence of grade II-IV acute GVHD was 47.8% with a 23.9% incidence of grade III-IV acute GVHD. Chronic GVHD was seen in 41.9% with a 15.4% incidence of extensive chronic GVHD. More than 90% had at least 1 documented infection with a 44% incidence of bacterial, 71% viral, and 38% fungal infection. The 2-year overall survival is 40.5% ± 3.2% with a higher survival among children (48.2% ± 3.4%) compared to adults (34.2% ± 4.1%). Survival was poor with late-stage disease (23.6% ± 4.3%) compared to early- (62.5% ± 7.5%) and intermediate-stage (50.3% ± 4.3%). Factors adversely affecting survival included older age of patient (P = .007), late disease status (P = .000), nonmyeloablative conditioning regimen (P = .003), bone marrow as graft source (P = .006), presence of acute GVHD (P = .069), primary graft failure (P = .000), and presence of a documented bacterial (P = .000) and fungal infection (P = .000). On multivariate analysis, older age (P = .027), presence of acute GVHD (P = .033), documented bacterial infection (P = .000), documented fungal infection (P = .000) and primary graft failure (P = .012) continued to remain significant. Haploidentical SCT offers a reasonable chance of cure for patients with both malignant and nonmalignant hematological diseases. Strategies to reduce aGVHD and infection related mortality needs to be explored further.© 20XX American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission

For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n = 257, 40%) or second complete remission (CR2; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated.

Impact of GvHD and Other Patient-, Disease-, Donor and Transplantation-Related Factors on 5 Year Relapse after Unrelated Cord Blood Transplantation for Children with Acute Lymphoblastic Leukemia in Remission

Relapse remains a major barrier to the long-term overall survival (OS) of pediatric patients with acute lymphoblastic leukemia (ALL). Allogeneic HSCT is a potentially curative option for these patients and its mechanism relies on graft-versus-leukemia (GvL) and delivery of high-dose chemotherapy. However, the mechanism and degree of GvL in curing ALL is not fully understood. Unrelated cord blood (CB) is an attractive donor option for these patients due to rapid procurement and lenient HLA matching without increased graft-versus-host disease (GvHD). Despite less GvHD, relapse is not increased when compared to other donor sources. Therefore, through collaboration between Eurocord, PDWP-EBMT and Duke University, we performed a retrospective analysis to identify risk factors associated with relapse, and the role of GvHD (as time dependent co-variate) in preventing relapse after unrelated CB transplantation (CBT) for children with ALL.We analyzed 640 children (<18 years (y)) with ALL in complete remission (CR) who received a single-unit CBT in either first (n=257, 40%) or second (n=383, 60%) CR from 2000-2012. Most patients were diagnosed with B-cell (79%) or T-cell (18%) lineage ALL and had no CNS involvement (92%). Cytogenetic data was available for 411 patients (CR1=171, CR2=240), and 37% were considered intermediate risk and 36% poor risk. Pre-transplant, 49% of patients were CMV seropositive. All patients received myeloablative regimens and most received anti-thymocyte globulin (88%). Regimens included total body irradiation (TBI; 69%) with either cyclophosphamide (Cy)+Fludarabine (Flu; 10%) or other agents (59%), Busulfan (Bu)+ Cy (16%), or Thiotepa+Bu+Flu (8%). Most patients received HLA mismatched CBs at 1 (50%) or 2+ (34%) loci. GvHD prophylaxis included cyclosporine with either steroids (72%) or mycophenolate mofetil (21%), or other agents (6%).Considering CR1 patients only, the median age at CBT was 5.3 y. Most were diagnosed with B-cell ALL (75%) and approximately half of those with known cytogenetics were considered poor risk. The median duration from diagnosis to CBT was 6.7 months and median follow up was 47 months. Estimated OS and LFS at 5 y for CR1 patients was 59% and 52%, respectively. Improved OS and LFS were associated with TBI-containing regimens and younger age at time of CBT (Table 1). The CI of relapse at 5 y was 23% for CR1 patients. In a multivariate analysis (MVA) the presence of acute GvHD (grade II-IV) and TBI-containing regimens were both protective of relapse (Table 1). No impact of GvHD was observed on OS, LFS or NRM.In CR2 patients, the median age at CBT was 6.9 y. Disease was primarily B-lineage ALL (82%) with intermediate or poor risk cytogenetics in 40% and 28% of patients, respectively. Median time from diagnosis to CBT was 36 months and median follow up was 54 months. Estimated OS and LFS in CR2 patients were 46% and 44%, respectively. In MVA, younger age and longer duration from diagnosis to CBT (>30 months) was associated with improved OS and LFS (Table 2). Conversely, the use of ATG was associated with lower OS.In CR2 patients, the CI of relapse was 28%. In MVA, longer duration from diagnosis to CBT (>30 months) and receiving TBI were both associated with less relapse. Importantly, receiving a fully matched HLA CB graft was a strong risk factor for increased relapse compared to mismatched CB recipients. Acute GvHD (II-IV) in this cohort was associated with higher mortality but not with relapse.In this large retrospective collaborative study, we investigated the impact of GvHD as a marker of GvL in pediatric ALL patients after CBT. In CR1 patients, acute GvHD and use of TBI were protective of relapse. However in CR2 patients, use of TBI, longer duration from diagnosis to CBT and HLA mismatched grafts were associated with decreased incidence of relapse but not with the presence of GvHD. These results showed that the impact of GvHD as a GvL marker is more evident in CR1 patients than CR2. Whereas, the impact of HLA mismatch CB on relapse is more important in CR2 patients. Decreasing immunosuppression more rapidly for CR1 patients or avoiding HLA identical CB for CR2 patients should be further investigated. In both cohorts, TBI has shown to be an important protective factor for relapse. [Display omitted] [Display omitted] DisclosuresBader:Riemser: Other: Institutional grants; Neovii: Other: Institutional grants; Medac: Other: Institutional grants; Amgen: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy.

Pre-transplant arm muscle area: a simple measure to identify patients at risk.

This study aims to explore parameters of nutritional assessment and food intake as predictors of clinical outcomes after hematopoietic stem cell transplant (HSCT). The study was conducted retrospectively with 56 adult patients undergoing allogeneic HSCT. Energy and protein daily intake were used to calculate the energy and protein cumulative deficit. The nutritional assessment tools were weight, body mass index (BMI), triceps skinfold (TSF), and arm muscle area (AMA) before HSCT and after HSCT. Food intake decreased immediately after the transplant and the energy and protein cumulative deficit increased during hospitalization (p < 0.01). Almost 70 % of patients had severe weight loss (greater than 5 %), and the average percentage of weight loss was 8.5 ± 3.9 %. BMI and weight loss percentage were not correlated with the presence of acute graft versus host disease (GVHD) and mortality within 180 days in this population. On the other hand, correlation was found between the initial (pre-HSCT) AMA equal to or below the 15th percentile, with the presence of acute GVHD (p = 0.024), and mortality within 180 days after HSCT (p = 0.010). The AMA measured pre-HSCT showed to be a potential predictor of acute GVHD and mortality up to 180 days after transplant in adult patients.

Serum Citrulline as a Biomarker of Gastrointestinal Function During Hematopoietic Cell Transplantation in Children

We sought to determine whether serum citrulline (CIT), an amino acid produced by small bowel enterocytes, was associated with clinical and biochemical markers of gastrointestinal function in children undergoing hematopoietic cell transplantation (HCT). We conducted a multicenter, prospective cohort study of 26 children to define time-related changes in serum CIT during the course of HCT. Markers of gastrointestinal function including oral energy intake, emesis, stool volume, presence of graft-versus-host disease (GVHD), oral mucositis severity, and cytokine and neurohormone levels were measured. Weekly serum CIT concentrations were obtained from 10 days prior until 30 days after HCT. Mean baseline CIT concentration was 22.7 μmol/L (95% confidence interval [CI] 17.7-27.6) on day -10, which decreased to a nadir of 7.5 μmol/L (95% CI 3.1-18.0, P = 0.017) on day 8 following HCT before returning to baseline by day 30. After adjustment for IL-6 level (1.0% lower CIT per 10% increase in interleukin-6, P = 0.004), presence of acute GVHD (27% lower CIT, P = 0.025), and oral energy intake (2.1% lower CIT per 10% decrease in energy intake, P = 0.018), the nadir shifted to day 10, when mean CIT concentration was lower in patients with severe oral mucositis (6.7 μmol/L, 95% CI 3.4-13.1) than in those without severe mucositis (11.9 μmol/L, 95% CI 5.8-24.4, P = 0.003). Change in CIT was not correlated with stool volume, C-reactive protein, tumor necrosis factor-α, leptin, or ghrelin. In children undergoing HCT, serum CIT correlates with measures of gastrointestinal function (oral mucositis severity, dietary intake, acute GVHD) and may reflect mucosal injury to the gastrointestinal tract.

Mixed Chimerism: Good News or Bad News?

Mixed Chimerism: Good News or Bad News?

Pulmonary Clinicopathological Correlation In Long Term Survivors Following Allogeneic Hematopoietic Stem Cell Transplantation: An Autopsy Series

BackgroundPulmonary complications are a significant cause of morbidity and mortality following Hematopoietic Stem Cell Transplantation (HSCT). It is estimated that they occur in 40-60% of patients, causing 10-40% of transplant-related deaths and resulting in diminished quality of life in those who survive. The wide spectrum of pulmonary complications is believed to be multifactorial, including pretransplant chemoradiation, infection, and graft-versus-host disease (GVHD). The histological spectrum of pulmonary GVHD features interstitial injury, airway injury (including bronchiolitis obliterans), and vascular disease (including veno-occlusive disease). The objective of this study was to compare ante mortem clinical suspicion of pulmonary complications and postmortem findings in a modern HSCT cohort. MethodsAll patients who underwent allogeneic HSCT at our institution (n=1854) between January 1, 2000 and June 30th 2010 were reviewed. To date we have completed the review of all autopsies (38) in patients who died of any cause greater than one year following HSCT. Presence of pulmonary GVHD was assessed by a pathologist blinded to the autopsy report, according to the categories of injury previously described by Yousem (1995). Lymphocytic infiltration and structural remodeling was scored separately for the airways, vasculature, and interstitium. Cases with extensive lung involvement by infection, malignancy, or other defined process (i.e. aspiration injury) were excluded from analysis. We evaluated the following clinical predictors for an association with development of airway disease and pulmonary vascular disease: patient gender, male patient with female donor, baseline FEV1%, peripheral blood stem cell source, myeloablative conditioning regimen, busulfan based conditioning regimen, patient CMV status, donor CMV status, related donor, matched donor, presence of acute GVHD, presence of chronic GVHD, and donor age. Each predictor was evaluated for significance between cases and controls. Two-sided Fisher's exact test was used to compare categorical variables between groups, and a 2-sided Wilcoxon Rank-Sum test was used to compare continuous variables. All statistical analyses were performed using SAS9.3. ResultsA total of 35 (92%) patients had evaluable pathology and were reviewed. Pulmonary complications were felt to contribute to death in 17 (49%) cases, and 28 (80%) of the patients had a diagnosis of chronic GVHD prior to death. Airway disease, interstitial disease, and vascular disease were all clinically under recognized compared to the number of cases detected on autopsy (table 1). Varying degrees of pathological changes were detected (table 2); including 10 (28.6%) patients having bronchiolitis obliterans (BO) and 12 (34.3%) patients having pulmonary veno-oclussive disease (PVOD). Of the patients with PVOD, 12 (86%) also had airway disease (p=0.07). In a univariate analysis, a positive cytomegalovirus (CMV) serology status in the patient was associated with the presence of airway disease (p=<0.002), and ablative conditioning (p=<0.01) and the presence of acute GVHD (p=<0.04) was associated with the presence of vascular disease.Table 1Disease Present on AutopsyDisease Suspected Ante mortemAirway Disease23/35 (65.7%)8/23 (34.8%)Interstitial Disease13/35 (37.1%)5/13 (38.5%)Vascular Disease14/35 (40%)1/14 (7.1%)Table 2Airway DiseaseLymphocytic bronchitis/bronchiolitis17/35 (48.6%)Lymphocytic bronchitis/bronchiolitis with intraluminal granulation tissue5/35 (14.3%)Bronchiolitis Obliterans10/35 (28.6%)Interstitial DiseaseCellular interstitial pneumonitis6/35 (17.1%)Organizing pneumonia6/35 (17.1%)Interstitial fibrosis8/35 (22.9%)Vascular DiseasePerivascular lymphoplasmacytic infiltrates3/35 (8.6%)Septal obliteration (PVOD)12/35 (34.3%) ConclusionsPulmonary manifestations of chronic GVHD, particularly BO, were clinically under recognized in our allogeneic HSCT population. Our results also suggest that pulmonary VOD, which has traditionally been considered a rare complication, may be clinically and histologically under recognized. A positive CMV serology status in patients was associated with the occurrence of airway disease. Ablative conditioning and the presence of acute GVHD was associated with the occurrence of vascular disease. Disclosures:No relevant conflicts of interest to declare.

Human Herpes Virus 6 Reactivation and Disease After Allogeneic Hematopoietic Stem Cell Transplantation

Background Human herpesvirus type 6 (HHV-6) is a member of the beta herpesvirus subfamily (genus Roseolovirus) and two distinct variants have been described: types A and B. HHV-6 infection is recognized as the cause of a febrile disease and exanthem subitum in early childhood. The infection rarely causes serious events in healthy individuals, but viral reactivation in immunocompromised patients is frequently associated with severe clinical manifestations. Above all HHV-6 is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic hematopoietic stem cell transplantation (AlloSCT). Approximately 60% of solid organ transplant and 40% of patients undergoing alloSCT experience HHV-6 reactivation, mainly of variant B. Reported clinical manifestations of HHV-6 infection in transplanted patients are skin rash, interstitial pneumonia, bone marrow suppression and encephalitis. Moreover, some clinical reports suggest that HHV-6 can facilitate the occurrence of severe clinical complications of alloSCT, increasing transplant-related mortality. Methods From January 2009 to February 2013, we retrospectively evaluated 54 consecutive adult patients (median age 50 years) who developed positivity to HHV-6 after alloSCT for high-risk hematological malignancies. Stem cell donors were family haploidentical (37), HLA identical sibling (8), unrelated volunteer (6), cord blood (3). The viral load was determined by quantitative PCR (Nanogen Advanced Diagnostic S.r.L) in cell-free body fluids such as plasma, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), bone marrow (BM) aspirates or in gastrointestinal biopsies. Results Median time from alloSCT to HHV-6 reactivation was 34 days (range: 0-705). Thirty-one patients presented HHV-6 positive in plasma, 9/54 in BM, 33/54 in gut biopsies or BAL, 7/54 in CSF. At the time of viral positivity all pts were receiving acyclovir as viral prophylaxis except five. Twenty-nine patients had acute graft versus host disease (GvHD). Twenty-two out of these twenty-nine patients experienced a grade III-IV acute GvHD, requiring high dose steroids in twenty-six cases. A concomitant CMV positivity was detected in 15/54 patients. The median absolute count of CD3+ lymphocytes was 262 cells/mcl. In 52/54 cases we reported HHV-6 clinical manifestations: fever (43), skin rash (22), hepatitis (19), diarrhoea (24), encephalitis (10), BM suppression (18), delayed engraftment (11). HHV-6 positivity led to antiviral pharmacological treatment in 37/54 cases, using as first choice therapy foscarnet. Amongst the total fifty-four patients with documented HHV-6 positivity thirty-one solved the clinical event. However the mortality rate was relatively high in this population (only 30% of patients were alive), mainly related to severe infections or GvHD. A better overall survival is significantly associated with CD3+ cells higher than 200/mcl (p-value 0.011) and time after alloSCT more than 2 months (p-value 0.035). In this analysis the overall survival was not significantly influenced by steroids administration, presence of acute GvHD, plasma viral load and organ involvement. Conclusions This retrospective study further demonstrates the correlation between HHV-6 reactivation and high morbidity and mortality rates in patients after alloSCT. Despite HHV-6 detection typically occurred in the first month after AlloSCT, a better immune reconstitution has the potential to improve the outcome. The regular monitoring of HHV-6 DNA, using a real-time PCR assay, may be useful for identifying active HHV-6 infection and for the introduction of a pre-emptive treatment, possibly reducing the incidence of the most severe clinical complications. Disclosures: Bonini: MolMed SpA: Consultancy.

Intensive Care Management and Outcomes In Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Aim Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used for the treatment of various hematological conditions with poor outcome. However, despite its effectiveness opportunistic infection, graft versus host disease (GVHD), drug toxicity and relapse frequently lead to life threatening complications and 15-20% of HSCT recipients ultimately require life sustaining therapies. Nowadays, a trend toward the use of less toxic conditioning regiments, different graft sources and better management of GVHD is observed. Also recent finding emphasize advances in the ICU management and triage policies of hematological patients. However, it is not known whether these changes altered the typology and outcomes of HSCT recipient admitted to ICU. We then performed a multicenter study to assess the impact of these changes. Methods All adults admitted in 3 ICU in Paris France from 1997 to 2011 were included if they previously received an HSCT. Data from medical charts were retrospectively retrieved and analyzed after the patients gave written informed consent. 497 patients were included, among whom 209 were admitted in the 1997-2003 period (this cohort was already published)1 and 288 in the 2004-2011 period. This corresponded to 2286 HSCT procedures over the same centers and period of time. Patients, HSCT characteristics and outcomes of the 2 cohorts were compared and prognostic factors analysis was performed in the recent period cohort. Results Over the time, HSCT recipients were more likely to be older (48 vs. 41 years old p&lt;0.001), transplanted with a reduced intensity conditioning (46% vs. 10% p&lt;0.001), peripheral blood mobilized stem cell (67% vs. 28% p&lt;0.001) and an unrelated donor (37% vs. 29% p&lt;0.001). ICU admission rate was 22% and remain stable over time (p=0,17). ICU admission triage was more frequent with less patients admitted with graft versus host disease (GVHD) stade over 2 (27% vs. 52% p&lt;0,0001) and absence of hematological remission (33% vs. 56% p&lt;0,0001). Admission occurred with a median time of 72 vs. 75 days after HSCT procedure with no difference over time p=0.68. Finally, organ dysfunction severity scores were not different between the 2 cohorts. We observed a significant survival improvement over the time as ICU, Day 90 and 1 year survival in the 2004-2011 cohort was respectively 71%, 49% and 37% vs. 48%, 31% and 21% previously. This was mainly due to improvements in the subset of patients requiring mechanical ventilation as shown in Figure 1. Also non-invasive ventilation use was similar between the 2 cohorts but more frequently successful (not followed by invasive ventilation) in the 2004-2011 cohort (51% vs. 33%). In the recent cohort, univariate analysis of Day 90 mortality showed that no demographic or HSCT parameter was associated with mortality. Only graft versus host disease (p&lt;0.001) and life sustaining therapies use (p&lt;0.001) CMV reactivation (p&lt;0.001) and invasive fungal infection (p=0.03) were found as mortality determinant. We then tested whether the strength of prognostic factors were changing with time using Gail and Simon interaction test and revealed that renal and respiratory failure and CMV reactivation were all three most strongly associated with mortality in the recent cohort. Logistic regression analysis revealed that, in the 2004-2011 cohort, the presence of acute GVHD stade &gt; 2, mechanical ventilation and renal replacement therapy were independently associated with day 90 mortality. Conclusion Despite improvement of ICU care in HSCT patients with no GVHD, this study show that life-sustaining therapy still remains mostly unsuccessful when used in patients with GVHD and deep immunosuppression. These data argue for a more rational policy of ICU admission triage in HSCT recipient 1Pene, Aubron, Azoulay et al. J. Clin. Oncol. February 1, 2006; 24(4): 643 - 649. Disclosures: No relevant conflicts of interest to declare.

Hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL): 25-year experience at the University of Minnesota

7001 Background: HCT is frequently used for management of ALL. Methods: We reviewed the records of 623 consecutive patients (63% male, median age 13 years) treated with myeloablative TBI-containing conditioning and either autologous or allogeneic transplantation between 1980 and 2005 at the University of Minnesota. Donor types were autologous (34%), related (45%), unrelated (16%) or cord (11%). Disease status at transplant was CR1 (24%), CR2 (50%), CR3 (18%) and relapse (8%). Univariate and multivariate analyses were performed for clinical endpoints including overall survival (OS), progression free survival (PFS), relapse, treatment-related mortality (TRM), and Grades II-IV acute and chronic graft versus host disease (GVHD). Results: Median follow-up among survivors was 8.3 years (1.0–22.9). The estimated incidence of acute GVHD was 42% and chronic GVHD was 16%. At 5 years, OS, PFS, and relapse were estimated at 29%, 26%, and 43% respectively. 5-year OS for each group: autologous (17%, 12–22%), related (35%, 29–41%), matched unrelated (42%, 29–55%), mismatched unrelated (21%, 11–33%), and cord blood (46%, 33–59%). TRM at 2 years was 28%. Multivariate analysis for OS, PFS, relapse and TRM for donor type is shown ( Table ). Acute GVHD was more frequent with unrelated donors (p&lt;0.01) but similar for related donors and cords. Presence of acute GVHD led to improved PFS (RR 0.6, 0.4–0.7, p&lt;0.01) and decreased relapse (RR 0.5, 0.3–0.8, p&lt;0.01) at 1 year. 5-year OS improved significantly from 1980–1984 (28%, 20–37%) to 2000–2005 (45%, 33–56%), p &lt; 0.01. Conclusions: Allogeneic HCT results in a durable PFS, although TRM is increased with unrelated mismatched donors. As expected, autologous HCT results in increased relapse rates. Despite significant mismatch, umbilical cord HCT led to similar OS, PFS, relapse, TRM and chronic GVHD compared to related donor HCT. Development of acute GVHD decreases relapse, resulting in improved PFS. No significant financial relationships to disclose. [Table: see text]

Posttransplant hematopoiesis in patients undergoing sibling allogeneic stem cell transplantation reflects that of their respective donors although with a lower functional capability

We tested the principle of whether patient long-term hematopoiesis following allogeneic stem cell transplantation (allo-SCT) reflects the characteristics of the hematopoiesis of their respective donor. For this purpose, we analyzed bone marrow (BM) hematopoiesis using long-term cultures (LTC), delta assays, and clonogeneic assays as well as CD34+ cells and their subsets by flow cytometry in a series of 37 patients undergoing allo-SCT, and we compared it to that of their respective human leukocyte antigen-matched sibling donors in a paired study performed more than 1 year after the transplant procedure. Interestingly, the main factor that influenced post-allo-SCT BM hematopoiesis in the long term was donor hematopoiesis. Nevertheless, compared to their respective donors, patients exhibited a significantly lower number of colony-forming units granulomonocytic, burst-forming units erythroid, and immature progenitors (CD34++/CD38dim/CD90+/CD133+ cells, LTC-initiating cells, and colonies generated in the delta assay). Moreover, BM stromal function was diminished in patients undergoing allo-SCT compared to their donors. In addition, the presence of chronic graft-versus-host disease under immunosuppressive treatment also conditioned an impaired hematopoietic function. In summary, our study shows that BM hematopoiesis evaluated more than 1 year after an allo-SCT mainly reproduces that of their respective donors, although with a significantly decreased in vitro activity.

High-dose acyclovir and pre-emptive ganciclovir in prevention of cytomegalovirus disease in pediatric patients following peripheral blood stem cell transplantation.

Cytomegalovirus (CMV) disease remains an important cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). We evaluated high-dose acyclovir (HDACV) and pre-emptive ganciclovir to prevent CMV disease in 76 children who underwent peripheral blood stem cell transplantation (PBSCT) and were at risk for CMV reactivation and disease (both recipient and donor seropositive) from May 1998 to April 2003. All received HDACV from day -9 to 6 months post transplant in conjunction with weekly CMV pp65 antigenemia monitoring. The incidence of antigenemia in this cohort was 19.7%, at a median of 22 days post-PBSCT. The frequencies were 26.4 and 4.4% in allogeneic and autologous groups, respectively (P=0.03). Patients with nonmalignant disease had higher CMV antigenemia than those with malignant disease (30.8 vs 8.1%, P=0.02). Age at PBSCT, sex, graft-versus-host disease (GVHD) prophylaxis regimen and presence of acute GVHD did not affect the risk of CMV antigenemia. None of the patients who had positive pp65 antigenemia developed CMV disease during the study period. We conclude that pp65 antigenemia-guided HDACV and pre-emptive ganciclovir may prevent CMV disease in children undergoing PBSCT.

Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells

AbstractReconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone marrow transplantation and is also dependent on the reestablishment of normal thymic structure and function. Graft-versus-host disease (GVHD), however, exacerbates posttransplant immunodeficiency through a deleterious effect on thymic function. To investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent→F1transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was associated with changes in thymic architecture and a reduction in cellularity mainly because of the decrease in CD4+CD8+, or double-positive (DP) thymocytes, to less than 15% of values found in mice without GVHD. Simultaneously, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was secondary to a decreased commitment of resident pro-T and pre-T cells to enter the cell cycle. Moreover, DP cells themselves showed altered proliferative capacities in the presence of acute GVHD. These findings suggested that thymic atrophy in acute GVHD is effected by impaired cellular proliferation of immature host thymocytes and that the failure of these cells to enter the cell cycle is dependent on an interferon (IFN)-γ–driven immune response. In contrast, interleukin-4–driven chronic GVHD was not accompanied by a sustained thymic infiltration of donor T cells. Consequently, there was a lack of apparent structural changes, a restricted in situ transcription of inflammatory cytokines, and a virtually unchanged cell cycle progression in vivo.

Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells

Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone marrow transplantation and is also dependent on the reestablishment of normal thymic structure and function. Graft-versus-host disease (GVHD), however, exacerbates posttransplant immunodeficiency through a deleterious effect on thymic function. To investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent-->F(1 )transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was associated with changes in thymic architecture and a reduction in cellularity mainly because of the decrease in CD4(+)CD8(+), or double-positive (DP) thymocytes, to less than 15% of values found in mice without GVHD. Simultaneously, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was secondary to a decreased commitment of resident pro-T and pre-T cells to enter the cell cycle. Moreover, DP cells themselves showed altered proliferative capacities in the presence of acute GVHD. These findings suggested that thymic atrophy in acute GVHD is effected by impaired cellular proliferation of immature host thymocytes and that the failure of these cells to enter the cell cycle is dependent on an interferon (IFN)-gamma-driven immune response. In contrast, interleukin-4-driven chronic GVHD was not accompanied by a sustained thymic infiltration of donor T cells. Consequently, there was a lack of apparent structural changes, a restricted in situ transcription of inflammatory cytokines, and a virtually unchanged cell cycle progression in vivo.

Cyclosporine as Possible Prophylaxis for Obstructive Airways Disease After Allogeneic Bone Marrow Transplantation

The objective of this study was to evaluate the impact of cyclosporine (cyclosporin A; CyA) prophylaxis for graft-versus-host disease (GVHD) on the development of obstructive airways disease (OAD) after allogeneic bone marrow transplantation (BMT) in leukemic patients. Patients with normal pulmonary function tests (PFTs) prior to BMT were followed with serial PFTs for the development of OAD. Follow-up PFTs were performed at 3, 6, 9, and 12 months, and thereafter at consecutive yearly intervals. Obstructive airways disease was defined as FEV1 less than 80 percent, ratio of FEV1 over the forced vital capacity (FEV1/FVC) less than 80 percent of predicted, maximal midexpiratory flow rate at 50 percent vital capacity less than 65 percent of predicted, or residual volume greater than 120 percent of predicted. In the period prior to CyA prophylaxis for GVHD development (March 1983 to September 1986), 17 (39 percent) of the 44 patients undergoing BMT developed OAD, compared with 2 (4 percent) of 45 in the post-CyA period (September 1986 to March 1990) (chi 2 = 17; p < 0.00005). Age, sex, type of leukemia, severity of GVHD, histocompatibility status, presence of acute GVHD, and sex mismatch between donor and recipient were not associated with development of OAD. Although chronic GVHD was associated with OAD in univariate analysis, a multivariate logistic regression analysis showed that the only significant independent predictor for OAD was the use of CyA. We conclude that CyA is protective against the development of OAD after BMT in leukemic patients.

Second allogeneic marrow transplantation for patients with recurrent leukemia after initial transplant with total-body irradiation-containing regimens.

The impact of a second marrow transplant on long-term disease-free survival (DFS) was evaluated for 77 consecutive patients aged 2 to 51 years who relapsed subsequent to allogeneic marrow transplantation after high-dose chemotherapy and total-body irradiation (TBI). Patients received a second transplant for recurrent chronic myelogenous leukemia (CML) (n = 28), acute myelogenous leukemia (AML) (n = 32), and acute lymphoblastic leukemia (ALL) (n = 15) or lymphoma (n = 2) that used the same marrow donor as the initial transplant. High-dose chemotherapy of busulfan (BU) and cyclophosphamide (CY), or CY, carmustine (BCNU), and etoposide (VP-16), was used as a preparative regimen for the second transplant. Graft-versus-host disease (GVHD) prophylaxis consisted of the following: no prophylaxis (n = 8), T-cell depletion (n = 36), methotrexate (MTX) only (n = 21), cyclosporine (CSP) only (n = 1), MTX and CSP (n = 9), or anti-thymocyte globulin (ATG) and prednisone (n = 2). Engraftment occurred in the 74 assessable patients. Severe veno-occlusive disease (VOD) was the most frequent cause of grades 3 and 4 regimen-related toxicity (RRT); it occurred in 20 patients. The probability of death before day 100 from nonleukemic causes was 36%. The probability of relapse after second transplant was 70%, and the DFS rate was 14% (median DFS, 36 months; range, 22 to 87). The DFS rates for ALL, AML, and CML were 8%, 10%, and 25%, respectively. Multivariate analysis showed that the risk of relapse was inversely associated with acute GVHD (relative risk [RR] of relapse = 0.2; P = .0009). No other factor was associated with relapse. DFS was associated with the presence of acute GVHD (RR of treatment failure = 0.5; P = .0085), and a reduction of DFS was associated with severe VOD (RR = 10.6; P = .0001) and those patients older than 10 years (RR = 2.5; P = .0337). These data show that some patients may benefit from a second marrow transplant for recurrent leukemia after an initial marrow transplant. Younger patients and patients with CML especially should be considered as potential candidates for a second transplant.

Phenotypical and functional studies on a subtype of suppressor cells (CD8+/CD11+) in patients after bone marrow transplantation.

Dual labeling with the monoclonal antibodies anti-Leu 2 (fluorescein-conjugated) and anti-Leu 15 (phycoerythrin-conjugated) was used to phenotype and sort the lymphocytes from 12 short-term (100 days postgrafting) recipients, 8 long-term (6 months postgrafting) stable, and 11 long-term patients with chronic graft-versus-host disease (GVHD). The proportion of Leu 2+ 15+ cells was increased in 11 of 12 short-term patients (mean + SEM: 31% +/- 3.6)-and in 6 of 11 patients with chronic GVHD (18% +/- 2.4) compared with normal controls (n = 8; 7.5% +/- 1.9). However, there was no correlation between proportions of Leu 2+ 15+ or Leu 2+ 15- cells and the presence of acute GVHD. Long-term patients with chronic GVHD tended to have a higher proportion of Leu 2+ 15- cells. To functionally characterize these two T cell subsets, Leu 2+ 15- and Leu 2+ 15+ subsets were sorted from purified T cells obtained from two recipients and one normal subject. Both Leu 2+ 15+ and Leu 2+ 15- cells from a short-term patient suppressed pokeweed mitogen--stimulated immunoglobulin production of normal B cells. Leu 2+ 15- cells from a long-term survivor with chronic GVHD and the normal control provided help, whereas the Leu 2+ 15+ cells also strongly suppressed immunoglobulin synthesis. The suppressor activity of the Leu 2+ 15+ subset in all three individuals was radiosensitive (12 Gy). These results illustrate the need for careful correlative phenotyping and functional studies. Furthermore, these studies clearly demonstrate that different functions may exist within a particular T cell phenotype after bone marrow transplantation.