Pre-Emptive Rituximab Treatment for Epstein-Barr Virus (EBV) Reactivation After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): High Incidence of Infections and Delayed Immune Reconstitution

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2303-2303
Author(s):  
Anna D. Petropoulou ◽  
Raphael Porcher ◽  
Regis Peffault de Latour ◽  
Alienor Xhaard ◽  
Patricia Ribaud ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Viral Infection ◽  
Immune Reconstitution ◽  
Fungal Infections ◽  
Conditioning Regimen ◽  
Significant Risk ◽  
Ebv Reactivation ◽  
Anti Cd20

Abstract Abstract 2303 Aim: Before pre-emptive treatment with Rituximab, the incidence of EBV-associated post-transplant lymphoproliferative disease (PTLD) was about 15 to 20% of patients (pts) following allogeneic HSCT with an 80% overall mortality. Rituximab (anti-CD20) in this context has dramatically decreased EBV-PTLD incidence. The aim of this single-center study was to evaluate the incidence on infections and on immune reconstitution following Rituximab for EBV reactivation. Patients and Methods: Sixty-nine pts received Rituximab for EBV reactivation at Saint-Louis Hospital (Paris, France) between January 2005 and January 2010, 44 males and 25 females, mean age 33 years (range, 10–68). Primary diseases were malignant hematopoietic disorders (70%) and aplastic anemia (30%). Fifty-two per cent received peripheral blood stem cells, 39% bone marrow and 9% cord blood. Myeloablative conditioning regimen was given in 71% of pts and reduced-intensity in 29%. Antithymocyte globulin (ATG) was given in 70% of pts before Rituximab therapy. EBV-quantitative polymerase chain reaction (PCR) was performed weekly during the first 3 months post-HSCT and then monthly until 1 year post-HSCT. Rituximab was administered weekly at the dose of 375mg/m2 after a positive PCR result (>10.000copies/ml) and discontinued as soon as a negative PCR result was available. Median time from transplant to Rituximab treatment was 43 days. Patients were followed-up until death or relapse. Median follow-up from the date of first Rituximab infusion was 27 months (range 4 to 61). Results: All treated pts cleared their EBV viremia after Rituximab. However, one patient developed PTLD despite Rituximab. Incidence of relapse was 5.9% (95%CI: 1.9–13.4) and non-relapse mortality was 41% (95%CI: 29–53) at 36 months. During follow-up, 43 pts developed a bacterial infection, 44 a viral infection and 16 a fungal infection. Infections occurred mainly during the first 12 months after Rituximab. The cumulative incidence of infection at 36 months was 64% (95%CI 50.7 to 74.6) for bacterial, 62.5% (95%CI 49.7 to 72.9) for viral and 24.6% (95%CI 14.7 to 35.8) for fungal infections. Reconstitution of lymphocytes, neutrophils and gammaglobulins after Rituximab therapy was assessed in the 36pts alive and relapse-free at 12 months. Starting from one month after initiation of Rituximab, lymphocyte counts gradually increased, by an average of 11.3% per month (95%CI 10.8 to 11.5; P<0.0001). Gammaglobulins significantly decreased during the first month after Rituximab, on average by 1.54g/L (95%CI 2.34 to 0.75; P=0.0002). After 3 months, a significant mean increase of 0.13 per month was observed (95%CI 0.01 to 0.26; P=0.037). CD19+ B and CD3+ T-lymphocytes reached normal values only at 1.5 years post-HSCT (median=172/μ L and 1339/μ L respectively at 1.5 years). Age, gender, stem cell source, type of donor, conditioning regimen, use of ATG and acute graft-versus-host disease (aGVHD) were assessed as possible risk factors for the development of infection. Acute GVHD grade≥3 or steroid-resistant aGVHD were statistically significant risk factors for bacterial (HR: 2.84, 95%CI: 1.12–7.23, P=0.028) or viral infection (HR: 4.03, 95%CI: 1.58–10.2, P=0.003). Cord blood transplantation and HLA-mismatch were significant risk factors for viral infection (HR: 2.62, 95%CI: 0.96–7.18, P=0.018 and HR: 3.47, 95%CI: 1.24–9.72, P=0.033 respectively). No significant risk factor was found for fungal infections. Conclusions: Rituximab pre emptive treatment has decreased PTLD incidence but is associated with high infection rate and prolonged immune defect. The question of over-treatment can be raised and further studies are needed to select candidates for pre-emptive treatment in order to avoid systematic anti-CD20 treatment and its later potential complications. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Incidence and Risk Factors for Nontuberculous Mycobacteria Infection after Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1917-1917 ◽  
Author(s):  
Jennifer M. Beswick ◽  
Elizabeth Shin ◽  
Jieun Uhm ◽  
Fotios V. Michelis ◽  
Auro Viswabandya ◽  
...  
Keyword(s):  
Risk Factors ◽  
Median Survival ◽  
Research Funding ◽  
Nontuberculous Mycobacteria ◽  
Fungal Infections ◽  
Conditioning Regimen ◽  
Significant Risk ◽  
Hematopoietic Cell ◽  
Survival Duration ◽  
Clinically Significant

Abstract Introduction: Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms that are increasingly recognized as clinically significant pathogens in the allogenic hematopoietic cell transplanted (alloHCT) population. The incidence of NTM infection post alloHCT has increased from 0.49-1.0% in early studies to 2.8-8.7% in more recent investigations, possibly due to improvements in NTM detection, varying pre-transplant conditioning regimens and regional epidemiology of different NTM species. We investigated incidence and risk factors of NTM infection after alloHCT. Methods & Patients: Medical records for 1097 consecutive patients who underwent alloHCT at Princess Margaret Cancer Centre from 2000 to 2013 were reviewed to determine the frequency, risk factors and outcomes associated with NTM infections. Clinically significant NTM infection was differentiated from colonization according to the American Thoracic Society guidelines, and was classified as pulmonary, non-pulmonary, or disseminated. Acute and chronic graft versus host disease (aGVHD and cGVHD) were diagnosed and graded using established and NIH consensus criteria respectively. The cumulative incidence of NTM was calculated considering competing risks of death. Multivariate analysis comprised Cox proportional hazards regression, modeling NTM risk. Statistical analyses were performed using EZR software (Saitama, Japan). Results: Of 1097 patients, NTM were isolated in 45 (4.1%) and judged clinically significant in 30 (2.7%). The incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9-4.0%). The median (range) time to diagnosis was 343 (19-1967) days, and in 83% of patients, was diagnosed within 2 years of alloHCT. Of the 30 clinically significant NTM infections, 28 (93.3%) were pulmonary and 2 (6.7%) were disseminated. With respect to the latter group, one patient had NTM isolated from blood, while the second case was presumed disseminated based on characteristic skin findings, but with no confirmed microbiologic diagnosis. The most common species/groups isolated were Mycobacterium avium complex (n=11, 36.7%), M. xenopi (n=5, 16.7%), and M. fortuitum (n=5, 16.7%). 22/30 patients (73.3%) were on systemic immunosuppression at the time of diagnosis, and 95.7% had concurrent infections (30.4% pulmonary, 17.3% extra-pulmonary, and 47.8% both), with fungal infections occurring most frequently (53.3%). Significant risk factors (HR 95% CI) for NTM included aGVHD grades 2-4 (3.25 [1.33-7.96] p=0.036), cGVHD (3.20 [1.06-9.68] p=0.010), age (1.05 [1.02-1.07], p <0.001), and CMV viremia (4.64 [1.90-11.37] p=0.001). 76.7% of patients with clinically significant NTM had a diagnosis of cGVHD (23/30), in comparison to 47.4% (520/1097) of patients without a diagnosis of NTM infection (p=0.003), and cGVHD severity by NIH global score correlated with NTM risk. Among all patients with cGVHD, severe cGVHD was present in 39% (9/23) of NTM patients, versus 17% (89/520) of non-NTM patients (p=0.012). Pre-alloHCT diagnosis (p=0.34), conditioning regimen (p=0.81), T-cell depletion (p=0.66), HLA matching (p=0.62), or donor type (p=0.63), did not reach statistical significance. Median survival duration after a diagnosis of clinically significant NTM was 398 (range, 20-764) days, with a survival rate of 40.8±10.8% at 2 years. Conclusion: Clinically significant NTM infection after alloHCT was relatively common in our study population. GVHD (acute and chronic), age, and CMV bacteremia were significant risk factors. Given a median survival of approximately 1 year following diagnosis, NTM infection may be of greater clinical significance than previously thought. A high index of suspicion for NTM infection in patients with pulmonary symptoms, particularly within 2 years after HCT and in the presence of cGVHD, may lead to prompt diagnosis and treatment, and potentially better outcomes. Disclosures Lipton: Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding. Kim:Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

Radioimmunotherapy (90Y-Zevalin®) Combined with BEAM Conditioning Regimen and Autologous Stem Cell Transplantation for the Treatment of Non Hodgkin Lymphomas: Results of An Italian Multicenter Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1144-1144 ◽  
Author(s):  
Vincenzo Pavone ◽  
Anna Mele ◽  
Antonio Rana ◽  
Cosimo Del Casale ◽  
Anna Rita Messa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Treatment Plan ◽  
Conditioning Regimen ◽  
Haematological Toxicity ◽  
Significant Risk ◽  
High Dose

Abstract Radioimmunotherapy (RIT) with 90Y-Zevalin® combined with high dose therapy and autologous stem cell transplantation (ASCT) is gaing increasing importance for the treatment of relapsed or refractory non Hodgkin Lymphoma (nHL). We evaluated the feasibility and the clinical results of the addition of 90Y-Zevalin® at standard dose to BEAM regimen (Z-BEAM) in nHL pts who failed to achieve complete remission (CR) after previous chemoimmunotherapy. Methods. Between October 2005 and June 2008, 53 patients were enrolled in 11 italian centers. The treatment strategy is shown in figure 1. Salvage treatment consisted of 2 courses of R-DHAP. PBSCs were collected after mobilization with DHAP and G-CSF plus in vivo purging with Rituximab. Patients’ characteristics are shown in table 1. Results. The median CD34+ cells infused was 5.5 x10^6/Kilograms (range 2.55–34). All patients engrafted. The median number of red blood cell and platelet transfusion were 4 (1–7) and 6 (1–8), respectively. The median time to platelet and neutrophil counts higher than 20x10^9/L and 0.5x10^9/L were 14 (range, 9–60 days) and 10 days (range, 8–20), respectively. Mucosites occurred in all pts (grade III in 20 and grade IV in 5 patients). Febrile neutropenia occurred in 39 pts (74%). Eight pneumonitis and 12 blood stream infections, mainly by Gram+, were documented. One patient developed an atrial fibrillation. Five pts were not evaluable for response because too early. The 90-day overall response rate was 86% with 74% of CR. Three relapses (relapse rate 9%) and four progression were documented at a median follow-up of 247 days post Z-BEAM (range, 125–818). The potential factor to predict CR was: at last PR before Z-BEAM (p=0.06). Fourthy patients are alive at a median follow-up of 175 days post HST (range, 6–590): thirty pts in CR (57%), three pts in PR (5.5%), three pts in progressive disease (PD, 6%)(fig. 2). Fourtheen pts died (26%): 5 deaths due to TRM before day 90, 1 for ARDS (+230), 1 TRM post a subsequent RIC allotransplant (+95) and 6 due to PD (median follow-up 110 days, range 97–150). The Kaplan-Meyer estimated 3y-EFS is 64%. Five early deaths before day-90 occurred: 2 due to septic shock (day +6 and +39), 1 to pneumonitis (+22), 1 for BK viral encephalites (+61) and 1 to MOF (+14). The Kaplan-Meyer estimated Treatment Related Mortality (TRM) is 9.3%. Two statistically risk factors for 90-day TRM (p&lt;0.03) were documented: age elderly then 65 and non follicular lymphomas histology. Cox multivariate regression analysis demonstrated that age more than 65 is a significant risk factor for TRM (3.4% in pts aged less then 65 years and 21,05% in older pts; p&lt;0.01). Conclusion. In pts with different histology nHL, who failed to achieve CR after previous immuno-chemotherapy, RIT integrated with high-dose chemotherapy (Z-BEAM) is capable to induce 86% of ORR, 74% of CR and 3 ys EFS of 64%, with sustained engraftment and an acceptable extra-haematological toxicity, mainly restricted to pts older then 65 ys. The power of this program needs to be assessed in a larger series of patients and in a randomized fashion. Table 1: Patient Characteristics and 90-day response post HST Figure. 1 Treatment Plan Figure. 1. Treatment Plan

Risk Factors for Mortality In Cytomegalovirus Infection After Hematopoietic Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4539-4539
Author(s):  
Fátima de la Cruz Vicente ◽  
Omar BenMarzouk-Hidalgo ◽  
Irene Gracia-Ahufinger ◽  
Raul García-Lozano ◽  
Manuela Aguilar-Guisado ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Viral Replication ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cmv Infection ◽  
Gvhd Prophylaxis

Abstract Abstract 4539 BACKGROUND: Cytomegalovirus (CMV) end-organ disease is a serious complication after allogeneic stem cell transplantation (Allo-SCT). Described risk factors for CMV infection are pretransplant CMV seropositive status of the recipient, non related donor or umbilical cord transplant, depleted lymphocyte graft, high intensity conditioning regimen, severe graft versus host disease (GVHD), CD34+ selection of the graft and delayed CMV specific immune reconstitution. OBJETIVES: To identify different profiles of allogeneic stem cell recipients based on their previously described risk factors for CMV infection and its association with their clinical outcomes. PATIENTS AND METHODS: A prospective study of consecutive recipients of Allo-SCT was performed from June 2008 through December 2009 at a single institution. Patients were sequentially monitored both clinically and analytically. CMV viral load was determined by real time PCR and CMV-specific T cell response was determined by flow cytometry. Non-normal distribution data were expressed as median values (range). Chi-square test or Fisher exact test were used to compare differences between groups of categorical data. Differences were considered statistically significant for p-values < 0.05. All statistical analyses were performed using SPSS 16.0 software (Chicago, IL). RESULTS: Twenty-six patients were included with a median age of 33 years (range:15-61). The donor was an identical sibling in 42.3%, unrelated donor in 53.8% and a mismatched family member in 3.8%. The source was peripheral blood 76.9%, cord blood 15.4% and bone marrow in 7.7%. Previous positive serostatus for CMV was 76.9% in recipients, and 53.8% in donors. The conditioning regimen was myeloablative in 57.7% and reduced-intensity in 42.3%. Graf versus host disease (GvHD) prophylaxis was cyclosporine (CsA) plus methotrexate (MTX) in 57.7% and CsA plus mycophenolate mofetil (MMF) in 42.3%. The incidence of acute GvHD was 76.9% and chronic GvHD was 53.8%. Treatment of GVHD was steroids plus CsA or tacrolimus and/or MMF in 76.9% of acute and 46.2% of chronic GvHD. Previously described risk factors for developing CMV infection were compared between patients developing (n=18) and non-developing (n=8) CMV infection. A higher risk for developing CMV infection was associated with previous CMV positive serostatus of the recipient (84% in viremic patients vs. 16% in non-viremic patients; p=0.01) and CsA plus MMF as GvHD prophylaxis (90.9% vs. 9.1%; p=0.04). We analyzed whether having several risk factors for developing CMV infection has an effect on the risk for developing CMV replication after the transplant. Patients that presented four or more risk factors, developed viral replication more frequently than patients having less than four risk factors (91.6% vs. 8.3%; p=0.02). Patients who acquired an earlier specific CMV immune reconstitution did not developed CMV replication, opposite to those with later immune reconstitution (week 2 vs. week 8, p= 0.01). Overall survival at one year was of 44.4% in the group with viral replication, and 100% in the group with no viral replication, p=0.014 (Figure 1). CONCLUSIONS: Patients that did not developed episodes of CMV replication after the transplant presented less than four risk factors for developing CMV infection, developed an early T-cell mediated CMV immune response and had better overall survival. The development of CMV specific immunity able to control CMV replication may be considered as a paradigm of post-transplant immune reconstitution with potential influence on overall survival. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3012-3012
Author(s):  
Hawk Kim ◽  
Sung-Soo Yoon ◽  
Chul Won Jung ◽  
Sang Kyun Sohn ◽  
Young Don Joo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Weight Gain ◽  
Hematopoietic Stem Cell Transplantation ◽  
Total Bilirubin ◽  
Conditioning Regimen ◽  
Significant Risk ◽  
Sinusoidal Obstruction Syndrome ◽  
Hematopoietic Stem ◽  
Hepatic Sinusoidal Obstruction Syndrome

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

Incidence of engraftment fever post autologous transplant for lymphomas and analysis of risk factors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7043-7043
Author(s):  
Avinash Pandey ◽  
Sushant S. Mittal ◽  
Ravi Thippeswamy ◽  
Deepan Rajamanickam K. ◽  
Anant Gokarn ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
White Cell Count ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Significant Risk ◽  
Autologous Transplant ◽  
Cell Dose ◽  
Cd 34 ◽  
Stem Cell Collection

7043 Background: Engraftment fever (EF) is a phenomenon observed in some patients undergoing autologous transplant (ASCT). We analyzed our data to evaluate the incidence and risk factors associated with EF. Methods: Seventy-nine patients underwent ASCT (53-Hodgkin’s and 26- Non Hodgkin’s) from August 2007 – January 2013. All except 5 received LACE (Lomustine, Ara-C, Cyclophosphamide and Etoposide) conditioning regimen. EF was defined as onset of fever with rising white cell count for which no infectious cause was ascertained. Patients of EF and non-EF groups were compared for the following variables to determine risk factors. These included histology, number of lines of chemotherapy regimens pre-transplant, complete remission (CR) at transplant, peripheral blood CD 34 count on day 1 of collection (PBCD34-D1), CD 34 cell dose collected and infused and number of days of stem cell collection. Results: The median age at transplant was 23.5 years with 57 males and 22 females. Time to neutrophil and platelet engraftment was 10 and 13 days respectively. EF was seen in 35 patients (44 %) at a median of 9 days. Short course of methylprednisolone (n=28) or hydrocortisone (n=3) was given to which all responded. On univariate analysis, PBCD34-D1 > 50/uL (P = 0.037), CD 34 cell dose infused >5.9x106/kg (P=0.012),CD34 cell dose collected > 7.2 x 10 6 /kg (P=0.032) , those receiving ≤ 2 lines of chemotherapy regimens before transplant (P=0.04), those who had ≤ 2 days of stem cell collection (P=0.002) and patients in CR at transplant (P = 0.015) were associated with risk of developing EF. On multivariate analysis, patients in CR at transplant and those who had ≤ 2 days of collection had higher risk of EF. Conclusions: The incidence of EF is high. Patients with lesser days of stem collection and those in CR at transplant have significant risk of developing EF.

scholarly journals Rapid and Safe T Cell Immune Reconstitution By T Cell Progenitor Injection Following Haploidentical Transplantation for Severe Combined Immunodeficiency (SCID)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1752-1752
Author(s):  
Despina Moshous ◽  
Elisa Magrin ◽  
Sarah Winter ◽  
Benjamin Fournier ◽  
Martin Castelle ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Post Transplantation ◽  
Historical Cohort ◽  
Hematopoietic Stem ◽  
Lymphoid Progenitors

Abstract Severe Combined Immunodeficiencies (SCID) are defined by a complete absence of T lymphocytes in the blood and lymphoid organs, with variable defects in other WBC subsets depending on the gene defect. From a clinical perspective SCIDs are characterized by early development of life-threatening infections accounting for early death if untreated. The treatment of choice is allogeneic HSCT with very high success rates if a HLA identical sibling (MRD) or unrelated donor (MUD) is used. However, due to the scarcity of matched-related donors, SCID can benefit from haploidentical HSCT. In contrast to the continuous improvement of HLA compatible donor transplantations, no significant improvements have been obtained over the last twenty years for haploidentical HSCT. The profound immunodeficiency during the first months following haploidentical HSCT exposes patients to opportunistic viral, bacterial and fungal infections, which account for approximately 30-40% of the transplant related mortality (TRM). The rapid restoration of the T-cell compartment is the main aim of stem cell therapy in this setting. To this end we have recently set up a phase I/II clinical trial (ClinicalTrials.gov Identifier: NCT03879876) aiming to accelerate the immune reconstitution by injection of ex vivo generated Human T lymphoid progenitors (ProTcell TM) following haploidentical HSCT. T cell progenitors in this trial are generated in vitro within 7 days from mobilized peripheral blood (mPB) CD34 + hematopoietic stem and precursor cells (HSPCs) using our Notch ligand Delta-like 4 GMP culture platform so called SMART Immune's SMART101 product. This open-label, non-randomized study evaluates safety and efficacy of the SMART101 injection following CD34 + selected, haploidentical HSCT in SCID patients and is designed as a dose-escalation study comprising 6 doses of the SMART101 product obtained from the patient's haploidentical stem cell graft. The aim of this protocol is to define the highest efficacy dose without any toxicity. The conditioning regimen is based on Busulfan and Fludarabine according to IE-WP/EBMT guidelines with upfront administration of ATG to prevent graft rejection. Tight monitoring of ATG serum levels is applied in order to assure injection of SMART101 when ATG is below the lymphotoxicity threshold. Here we report the results of the first two SCID patients. P1 presented a homozygous Artemis deficiency. At diagnosis he had an ALC of 341/µl, with complete absence of T cells (CD3 + &lt; 4/µl, CD4 + &lt; 1/µl, CD8 + &lt; 2/µl) and B cells (CD19 + 0/µl). NK cells were present in the normal range for age (CD16 +CD56 + 331/µl). In the absence of an HLA compatible donor, the patient`s father was chosen as haploidentical stem cell donor. P1 received upfront ATG (5 mg /kg total dose), Busulfan (AUC of 16058 microM.min) and Fludarabine (160 mg/m²). He received Defibrotide prophylaxis from D0 until D+21, as well as Ursodeoxycholic acid until D+80. The CD34 + immunoselected graft contained 1.04 x 10 8 nucleated cells/kg with 24.15 x10 6 CD34 + cells/kg and 4000 CD3 + cells/kg on D0. After ATG monitoring 0.12x10 6 Smart101 cells were administered at D+14 post- HSCT. In the follow-up P1 didn't develop any acute or chronic SAEs, no acute or chronic GVHD, and no infection. He was discharged at D+121 post HSCT. The day +100 post transplantation CD4 + cell count/microliter exceeded 10 times the CD4 + count of our historical cohort of RAG1/2 or Artemis deficient patients transplanted with haploidentical HSCT alone following the same conditioning regimen. At 6 months post HSCT this difference remains important (851 versus 300 CD4 + cells/µl); Ig replacement therapy could be stopped as early as 9 months post transplantation and vaccinations have been started. At last follow up; almost 14 months post HSCT P1 is alive and well. P2 had an undefined molecular SCID diagnosis. She has been treated with the same conditioning regimen and received the second dose of 0.2x10 6 CD7 + cells, but unfortunately died from severe VOD emphasizing the need to replace chemotherapy with less toxic myeloablative agents. The preliminary results obtained after injection of Human T lymphoid progenitors in P1 are encouraging. While deserving confirmation in larger numbers of patients they could represent an important step forward in improving the outcome of haploidentical HSCT for SCID. Disclosures Cavazzana: Smart Immune: Other: co-founder.

Long Term Psycho-Social Aspects and Risk Factors for Severe Infections, Ocular, Pulmonary, Bone, Thyroid and Other Complications after Allogeneic Hematopoietic Stem Cell Transplantation for Children with Hematologic Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3371-3371
Author(s):  
Christèle Ferry ◽  
Gladys Gemayel ◽  
Vanderson Rocha ◽  
Myriam Labopin ◽  
Hélène Esperou ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Social Aspects ◽  
Pulmonary Dysfunction ◽  
Hematopoietic Stem ◽  
Severe Infections

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for children with hematologic malignancies. However, many long term complications are observed with a longer follow-up. Few data is available analyzing psycho-social aspects and risk factors of various long term complications in a same cohort of children. We have reviewed the charts of 112 children younger than 16 years, transplanted for hematologic malignancies between 1985 and 2000 at Saint Louis Hospital, and who survived at least 1 year after transplant. Landmark analysis and cumulative incidence using death and relapse as competing events were used to calculate incidences of complications after one year of HSCT. Univariate analysis used the Fine and Gray test and multivariate Cox model was used with chronic GVHD (cGVHD) as time dependent variable. Results: Median age at transplant was 8.3 years (0.73–15 years), median follow-up from 1 year after transplantation was 8 years (0.3–16.5). Most frequently, children had acute leukemia (n=101, 90%) and 92 patients were transplanted with an HLA-identical sibling donor.Total body irradiation (TBI) was used in 87 patients as part of conditioning regimen and fractionated TBI was used since march 1994 in 37 patients. At 10 years, overall survival was 75±5%, transplant related mortality (TRM) was 18%±4 and relapse 14±3%. Ten year cumulative incidence of severe infections (mostly bacterial) was 31%±4 (n=33); it was 44±4% for cataract (n=48); 20±4% for pulmonary dysfunction (mostly restrictive abnormalities) (n=20); 29±5% for osteoarticular complications (mostly osteonecrosis) (n=27); 36±4% for hypothyroidism (n=36); 11±3% for cardiac complications and 7±3% for secondary malignancies (n=8). The number of complications per patient increased with time, from 1 at a median observation time of 73 months to 3 at a median of 120 months. Factors related to patient, disease, donor and transplant characteristics were analyzed in univariate and multivariate analysis for complications with at least 20 events. There was a trend of higher risk of TRM (p=0.06), osteoarticular complications (p=0.09) and infections (p=0.07) for patients presenting cGVHD. cGVHD was significantly associated with higher risk of pulmonary dysfunction (p=0.02). However, single dose TBI (sTBI) or only TBI was the most important factor among other factors that increased the risk of cataract (p<0.001), pulmonary (p=0.004), osteoarticular (p=0.04) and thyroid complications (p<0.0001).Concerning psychological health and social issues; half of the patients had psychological disturbance, 13 patients had signs of depression, 16 history of eating behavior disorders. Half of the patients who had more than 18 years had an employment, 36 patients achieved normal scholarship, 69 had scholar difficulties and 12 patients achieved superior level studies. In conclusion with a longer follow-up in survivors of HSCT long term complications become an important issue. These complications reached no plateau even after 10 years. Development of less toxic conditioning regimen, avoid sTBI and probably better control of cGVHD may prevent late effects and improve quality of life of long term survivors.

Efficacy and Safety of Micafungin for Prophylaxis of Invasive Fungal Infections in Patients Undergoing Haplo-Identical Hematopoietic Stem Cell Transplant

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4505-4505
Author(s):  
Jean El-Cheikh ◽  
Geoffroy Venton ◽  
Roberto Crocchiolo ◽  
Sabine Furst ◽  
Catherine Faucher ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Ct Scan ◽  
Disease Progression ◽  
Fungal Infections ◽  
Conditioning Regimen ◽  
Median Number ◽  
Invasive Fungal Infections ◽  
Efficacy And Safety

Abstract Abstract 4505 Invasive fungal infections (IFI) such as candidiasis and mold infections cause significant morbidity and mortality among immunocompromised patients in recent years. Micafungin, a new echinocandin, inhibits fungal cell wall beta-glucan synthesis, with potent activity against most species of Candida and Aspergillus. The aim of this observational study was to investigate the efficacy and safety of Micafungin in prophylaxis of invasive fungal infections (IFI) in 20 high risk adult patients with various haematological diseases receiving haplo-identical allogeneic stem cell transplantation (Allo-SCT). Treatment success was defined as no proven, probable, or suspected IFI through therapy and the absence of proven or probable IFI through the end of 12 weeks after therapy. (EORTC criteria). These patients were monitored after Allo-SCT for galactomannan antigenemia at least once per week, and a computed tomography (CT) scan was performed in the case of persistent fever for at least 5 days after broad-spectrum empirical antibacterial therapy. Routine controls (e.g. detection of galactomannan antigenemia and CT scan) were performed systematically after 1 and 2 months and on day 100 after Allo-SCT. Only 2 patients had a history of possible aspergillosis before transplant treated by voriconazole. The patients received a median of 4 lines (2–7) of treatments before Allo-SCT. Ten patients (50%) received at least one auto-SCT; and 5 patients (25%) received a previous Allo-SCT. 18 patients (90%) received a reduced intensity conditioning regimen (RIC), with Fludarabine, Cyclophosphamide and Total body irradiation (TBI) 2 Gy based (75%), or Fludarabine, Busulfan, and Cyclophosphamide based (10%) or other (5%). while two patients (10%) received a myeloablative conditioning regimen with thiotepa. The patients and transplant details are shown in the table 1. Patients received a median of 26 infusions (range, 1–8) of Micafungin (50 mg/day i.v. as a 1h infusion). The treatment was initiated at the beginning of the transplant conditioning regimen until the hospital discharge. None of our patients discontinued the treatment for drug-related adverse events. Micafungin was not associated with any hepatotoxicity. Only one patient (5%) discontinued the treatment because an early disease progression. At last follow-up, there are 17 patients (85%) who are alive, with a median follow-up of 6 months (3–17). Three patients (15%) dead because disease progression. In all patients no candidas and/or Aspergillus species was documented after 3 and 6 months from transplant. None of our patients presented a positive galactomannan antigenemia >0.5. Seven patients (35%) presented a CMV reactivation. Only one patient presented an acute GvHD grade II. Micafungin has a good safety and tolerability profile, with an efficacy in preventing IFI in this high risk population. Our data provide support for an efficacy study in a prophylaxis setting, but prospective and comparative clinical trials using Micafungin are urgently needed to define the role of this drug in prophylaxis after haplo-identical Allo-SCT. Table 1. Patient and transplantation characteristics Patient and transplantation characteristics n = 20 (%) Patients Age (median) [range] 40 years (range, 20–60) Patients sex Male 12 (60) Female 8 (40) Disease type HL 6 (30) NHL 5 (25) AML 4 (20) MM 2 (10) MF 1 (5) MDS 1 (5) CLL 1 (5) Median number of prior chemotherapies before Allo-SCT [range] 4 (2–7) Median number of prior Auto-SCT [range] 1 (0–2) 1 8 (40) 2 2 (10) Status of disease at Allo-SCT >2 CR 11 (55) PR 6 (30) PD 3 (15) Median interval between auto and Allo-SCT months [range] Donor type Brother 8 (40) Mother 6 (30) Sister 3 (15) Son 2 (10) Father 1 (5) Donor/recipient sex mis match 9 (45) Conditioning regimen Flu 5+Cy 2+ TBI 15 (75) Flu 5 +Cy 2+ Bu 2 2 (10) Flu 3+TT 2+ Bu 3 2 (10) Flu 6+ Cy 1+ ATG 4 1 (5) GvHD prophylaxis CSA+MMF+Cy 20 (100) Stem cell source Peripheral Blood 11 (55) Bone Marrow 9 (45) Stem cell dose median [range] CD34+ × 106/kg 4,25 (0,8–10,8) CD3+ × 106/kg 140 (17–411) Days with ANC< 500 × 109/l 21 (14–49) Days with platelets<20 × 109/l 26 (14–140) Disclosures: No relevant conflicts of interest to declare.

Early and Favourable Immune Reconstitution After Unmanipulated Haploidentical Stem Cell Transplantation With High Dose Post-Transplant Cyclophosphamide Regardless Intensity Of Conditioning Regimen

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4620-4620
Author(s):  
Isabel Gonzalez-Gascon y Marin ◽  
Ana María Pérez-Corral ◽  
Jorge Gayoso ◽  
Javier Anguita ◽  
Ana Carolina Franco ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
High Dose ◽  
Post Transplant ◽  
Haploidentical Stem Cell Transplantation

Introduction Favourable immune reconstitution (IR) has been reported after reduced intensity conditioning (RIC) Unmanipulated Haploidentical Stem cell transplantation (Haplo SCT) with high dose post-transplant cyclophosphamide, and it has been suggested as a relevant factor for the good clinical outcomes observed. Due to the encouraging results in our centre the intensity of conditioning regimen has been increased in some patients with high risk of relapse. The aim of this study is to analyze whether the increase in intensity of conditioning influences immune reconstitution after Haplo-SCT. Methods and patients 22 patients (pts) with high risk hematologic malignancies treated in our centre with Haplo-SCT from 2007 to 2013 were included in the analysis. 8 pts received myeloablative(MA) conditioning regimen(fludarabine 30 mg/m2 IV (day -6 to -3) and busulfan 3.2 mg/kg IV (day -6 to -3) or fludarabine 30 mg/m2 IV (day -6 to -2), cyclophosphamide 14.5 mg/kg (day -6 to -5), and busulfan 3.2 mg/kg IV (day -4 to -2)). 14 pts received RIC conditioning regimen (fludarabine 30 mg/m2 (day -6 to -2), cyclophosphamide 14.5 mg/kg (day -6 and -5), and busulfan 3.2mg/kg IV (day -3 or day -4 to -3)). GVHD prophylaxis was high dose cyclophosphamide on days +3 and +4, cyclosporine A and mycophenolate mofetil for all patients. Median age was 43 years (26-65) and underlying diseases included: AML (8); ALL (1); MDS (2); MM (2); Hodgkin´s disease (7); mantle cell lymphoma (1); accelerated myelofibrosis (1). Median follow-up was 16 m (5-53). 13 pts were alive and disease-free at last follow-up and 4 pts died (3 relapse, 1 progressive multifocal leukoencephalopaty). We evaluated lymphocyte subsets (absolute numbers of CD3, CD4, CD8, CD19, NK, NKbright, and CD19) by flow cytometry (FC500 Beckman Coulter® cytometer) at 1, 3, 6, 9 and 12 months (m) post Haplo-SCT in the two groups (MA and RIC conditioning regimen). Immunoglobin serum levels were recorded at the same time points. For comparison Mann–Whitney U-test was used. Results In the 22 pts, NK cells were the first lymphocyte subset to recover with a median of 84/μl (5-480) and 145/μl (12-562) by m1 and m3 respectively. A high proportion of NKbright cells was observed at m1 post-transplant. This NKbright population decreased from a median of 83% (15-95) at m1 to 32% (9-95%) at m3, and 30% (9-57%) at m6. CD3+ T-lymphocytes (TL) reached normal levels at m3 after haplo-SCT (median 1109/μl (40-3187), and remained at normal range throughout the study period. CD4+ reached levels > 200/μl at m3 with a median of 247/μl (1-570), and also remained above this threshold during the follow up. Reconstitution of CD19+ B lymphocytes was adequate, with a median of 2/μl (0-76); 91/μl (0-556); 139/μl (3-600); 238 (105-575) and 236/μl (12-1098) on m1, 3, 6, 9 and 12 respectively. No difference was observed between RIC and MA conditioning for NK, NKbright; CD3+, CD4+, CD8+ T-lymphocyte and CD19+ B-lymphocyte count recovery. IgM was the first immunoglobulin to recover, reaching normal levels by m3 (61 mg/dL (10-264)), followed by IgG (normal levels at m12 (692 mg/dL (242-1530)). IgA reconstitution was delayed and did not reach normal levels by m12, as described before. No difference was found between RIC and MA conditioning for immunoglobulin recovery. Table 1 shows IR after haplo-SCT. Conclusions Rapid and favourable immunologic recovery was observed after haplo-SCT as reported before. Intensity of conditioning did not have any significant impact on the kinetics of immune recovery. Acknowledgments This work has been partially supported by Project “Evaluación de la reconstitución inmune después del trasplante haploidéntico de progenitores hemopoyéticos sin depleción T” from Fundación Mutua Madrileña. Disclosures: No relevant conflicts of interest to declare.

Second Stem Cell Transplantation for Relapse of Childhood Hematologic Malignancies Following Initial Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3448-3448
Author(s):  
Nao Yoshida ◽  
Nobuhiro Watanabe ◽  
Kimikazu Matsumoto ◽  
Hirotoshi Sakaguchi ◽  
Asahito Hama ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Risk Factor ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
Significant Risk ◽  
Hematologic Malignancies ◽  
Stem Cell Source ◽  
Cell Source ◽  
Donor Type

Abstract Abstract 3448 Treatment options for patients with hematologic malignancies who relapsed after stem cell transplantation (SCT) are limited. Second SCT could be an effective salvage therapy in some patients who relapsed after initial transplantation. However, most studies of second SCT have focused on adult patients, and the significance of this treatment option in pediatric cohorts is largely unknown. To identify prognostic factors, we retrospectively evaluated the outcome of second SCT in 44 children (25 boys and 19 girls) with hematologic malignancies who received second SCT for disease recurrence after initial transplantation between September 1986 and January 2008 at three transplant units in Nagoya, Japan. The influence of potential risk factors on overall survival (OS), disease-free survival (DFS), relapse rate (RR), and non-relapse mortality (NRM) was assessed using Cox proportional-hazards regression model, taking the background of the first and second SCT into account. Median age at second SCT was 9 years (range, 1–18 years). Underlying diseases were AML/MDS in 22 patients and ALL/ML in 22 patients. Disease status at second SCT was complete remission (CR) in 18 patients and non-CR in 26 patients. Median time from first SCT to relapse and second SCT was 6 months (range, 1–84 months) and 11 months (range, 4–92 months), respectively. For the first SCT, donor type was autologous (n=14), related (n=21), or unrelated (n=9), the stem cell source was peripheral blood (PB) in 6 patients, bone marrow (BM) in 37, or cord blood (CB) in 1, and conditioning regimen was myeloablative (n=35) or non-myeloablative (n=9). For second SCT, donor type was related (n=20) or unrelated (n=24), the stem cell source was PB (n=2), BM (n=39), or CB (n=3), and conditioning regimen was myeloablative (n=37) or non-myeloablative (n=7). Overall, 10 patients were alive with a median follow-up of 67 months from second SCT, and the probability of OS at 5 years was 22%. The 5-year DFS, RR, and NRM was 19%, 53%, and 55%, respectively. Of the 44 patients, 34 patients died following second SCT; 14 patients died owing to relapse and 20 from complications. The survival of patients with non-CR status at second SCT was significantly inferior to survival of patients in remission (8% vs. 40%; P = .01). Notably, all 14 patients who died after relapse were not in remission at second SCT. In multivariate analysis, non-CR at second SCT was the only risk factor for survival (P = .01). In addition, non-CR at second SCT (P = .005) was the most significant risk factor for relapse, and followed by use of unrelated bone marrow as source of stem cells at first SCT (P = .01) and age at second SCT of ≥10 years (P = .01). No significant risk factors were identified for NRM. In summary, second SCT offers only limited chance of cure for patients with a history of unrelated bone marrow transplantation at first SCT or non-CR status at second SCT. On the other hand, the results of this study indicate that second SCT represents a sufficiently effective therapeutic option for the subset of children who are in remission at second SCT, with 40% of long-term survival. Disclosures: No relevant conflicts of interest to declare.

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