Fatal Infectious Complications Developing Late after Allogeneic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3239-3239
Author(s):  
Andreas Bjorklund ◽  
Johan Aschan ◽  
Olle Ringden ◽  
Jacek H. Winiarski ◽  
Per T. Ljungman
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Control Group ◽  
Cmv Infection ◽  
Respiratory Dysfunction

Abstract Background and aim: The procedure of allogeneic stem cell transplantation (SCT) has evolved during the past decades. Infectious complications are still a major problem contributing to the transplantation related mortality (TRM). The epidemiology and outcome of early infections after SCT are well described. However, less is known has about late infections after SCT. Thus, the aim of this study was to determine risk factors for fatal infections occurring later than 6 months after allogeneic SCT. Material and methods: Our study is based on 938 consecutive SCT patients transplanted 1976–2003 of whom 688 (73%) had survived for at least 6 months after SCT. A retrospective chart review was performed identifying 44 (6.4%) patients surviving for at least 6 months, having died from infection. Patients who had relapsed in their malignant disease were excluded. A control group of 176 patients (4 per case) was identified using relapse-free survival for at least 6 months and year of SCT as the matching criteria. Five controls were excluded leaving 171 patients in the control population. Risk factors for death from late infections were identified by logistic regression. Results: 29 patients (66%) developed their fatal infection within 18 months and 37 (84%) within 5 years after SCT. 37 patients (84%) had ongoing chronic graft versus host disease (GVHD) and 36/44 (82%) had ongoing immunosupression at the time of death. 57 controls had died after 6 months from SCT; 32 of 57 from relapse. Comparing patients and controls in univariate analyses, the mean age was 30.6 years in the cases and 26.5 years in the controls (p=.13). 22/44 (50%) cases had been transplanted from an unrelated or mismatched donor, compared to 57/171 (33%) controls, p=.053; and 35/44 (80%) cases had received a conditioning regimen including myeloablative dose of TBI compared to 113/171 (66%) in the control group, p<.05). Regarding post-transplant complications 40/44 (91%) cases had experienced cGVHD compared with 101/171 (59%) controls, p<.001. 21/44 (48%) cases had developed obstructive respiratory dysfunction compared with 46/171 (27%) controls, p=.01; and more cases (33/44; 75%) than controls (85/171; 50%;) had experienced CMV infection. In multivariate analysis chronic GVHD (OR 9.2; p<.001), use of a mismatched or unrelated donor (OR 4.8; p<.001), and having had a CMV reactivation (OR 8.3; p=.004) increased the risk. Age, acute GVHD, TBI or obstructive respiratory dysfunction had no significant impact on the risk for late fatal infection. Conclusion: Infections later than 6 months after SCT are important contributors to late TRM. Risk factors for late fatal infections include chronic GVHD, use of alternative donors and CMV infection.

Gene Polymorphism Profile May Predict Late Complications In Patients Undergoing Allogeneic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3321-3321
Author(s):  
Lidia Gil ◽  
Marzena Wojtaszewska ◽  
Anna Mol ◽  
Krzysztof Lewandowski ◽  
Jan Styczynski ◽  
...  
Keyword(s):  
Stem Cell ◽  
Gene Polymorphism ◽  
Stem Cell Transplantation ◽  
Bacterial Infection ◽  
Fungal Infection ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Cmv Infection

Abstract Gene polymorphism analysis may predict infection development, especially invasive fungal disease, in recipients of allogeneic stem cell transplantation (alloSCT), as previously reported (Gil et al., BMT 2013). It is also suggested that gene polymorphism may contribute to non-infectious complications occurrence. Objective Analysis of late complication after alloSCT with respect to gene polymorphism profile. Material and Methods Analysis for infectious or non-infectious complications was performed in a cohort of 126 adult patients (pts) with acute leukemias (94), chronic leukemias (10) or lymphoid malignancies (22) who underwent alloSCT and survived at least 100 days. All pts and their sibling (58) or unrelated (68) donors were previously screened for TLR4, IFNG, TNFR2 and DECT1 single nucleotide polymorphisms (SNP). The primer for TLR4 SNP was designed using Lasergene Primer Select. IFNG, TNFR2 and DECT1 polymorphisms were screened with published primers with PCR conditions common to all reactions. Patients were conditioned with myeloablative (58) or reduced intensity (68) regimen and grafted with 3.8 (0.8-5.2)x10^6/kg of CD34+ cells. Standard definitions for relapse, graft versus host disease (GVHD) and infections (neutropenic, bacterial, fungal and viral) were used. Results Infectious complications that occurred after 100 days posttransplant included bacterial infection in 28 (22%), CMV infection in 19 (15%) and invasive fungal infection in 12 (9%) pts. Late onset acute GVHD 2-4 grade was seen in 15 (12%), while chronic extensive GVHD in 18 (14%) pts. Relapse was diagnosed in 30 (24%) pts. Secondary malignancies were observed in 2 pts. Over a median follow-up of 34.5 (range; 6-85.5) months, 90 (71%) pts were alive with median survival 35.5 (95% CI=8-87) months. Among genetic factors by multivariate logistic regression analysis donor DECT1 SNP was significant for fungal infection development (p=0.016, HR 5.7); chronic GVHD development (p=0.038, HR=4.4) and death from chronic GVHD (p=0.028; HR=4.8). Additionally, donor INFG SNP was significant for CMV occurrence (p=0.019; HR=5.5). None of studied polymorphisms had impact on the outcome. Among transplant-related factors (age, sex, diagnosis, disease stage, dose and source of stem cells, type of transplant, intensity of conditioning, neutropenia duration) only alloSCT from unrelated donor was significant for late CMV infection (p=0.47; HR=3.9) and bacterial infection (p=0.036; HR=4.4) development. Conclusion Our results suggest that gene polymorphism profile may predict late infectious and non-infectious complications in patients undergoing alloSCT. It may influence stratification of pts to offer an individualized therapy. Disclosures: No relevant conflicts of interest to declare.

Effect of Rituximab on the Incidence of GVHD in Lymphoma Patients who Received the BEAM-Conditioning and an Allogeneic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4980-4980
Author(s):  
Issa F. Khouri ◽  
Rima M. Saliba ◽  
Daniel R. Couriel ◽  
Grace-Julia Okoroji ◽  
Sandra Acholonu ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Control Group ◽  
Study Group

Abstract It has been postulated that B cells functioning as antigen-presenting cells may have an important role in the pathogenesis of GVHD. Depletion of donor cells from B-cells resulted in a low incidence of GVHD in mouse model (Schultz et al. BMT1995:16:289–289). More recently, we observed a lower incidence of chronic (and to a lesser extent acute GVHD) in patients with CLL who received an allogeneic stem cell transplantation after a non-myeloablative conditioning regimen containing rituximab (Exp Hematol32:28–35, 2004). The purpose of this study is to investigate the effect of rituximab on GVHD in the setting of a more intense chemotherapy with BEAM, in patients who received an allogeneic peripheral blood stem cell from HLA-identical siblings. To test this hypothesis, we retrospectively studied 11 consecutive patients with non-Hodgkin’s lymphoma who received BEAM/Rituximab at the M. D. Anderson Cancer Center. We attempted to match these patients by age, donor-recipient gender, and donor-recipient CMV reactivity to a historical control of 44 patients with lymphoma, who received BEAM alone as a conditioning regimen, without the Rituximab. Tacrolimus and methotrexate were used for GVHD prophylaxis in both groups. A total of 10 patients in the study group, could be matched with 19 patients in the control group and were included in the final analysis. The outcome of the 2 groups is shown below: Rituximab-Study Group Control Group -value P No. of patients 10 19 Median age 41 44 0.4     (range) (19–55) (19–60) Patient-Donor sex-matched 9(82%) 18(95%) 0.6 Median # CD34 + cells infused (106/kg) 5.1 4.73 0.1 Patient or Donor CMV+ 9(82%) 18(95%) 0.6 Patient and Donor CMV − 1(10%) 1(5%) Median # prior chemoregimens 3 3 0.9     range (1–8) (1–9) Median follow-up 17 38     range (8–48) (27–77) Acute GVHD 2–4 (n,%) 5(50%) 7(37%) 0.5 Acute GVHD 3–4 (n,%) 3(30%) 5(26%) 0.6 Chronic GVHD (n, % cumulative incidence) 8 (90% + 15) 10 (53% + 12 0.01 Our data suggest that the described protective effect of Rituximab against GVHD in mouse models or in the setting of non-myeloablative allogeneic transplantation, may be overcome by the BEAM. This more intense conditioning regimen may induce more GVHD by enhancing T-cell cytokines release and by causing more gastrointestinal toxicity, thus allowing for a greater antigen presentation.

Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 1977-1983 ◽  
Author(s):  
Tapani Ruutu ◽  
Britta Eriksson ◽  
Kari Remes ◽  
Eeva Juvonen ◽  
Liisa Volin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Ursodeoxycholic Acid ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Treated Group ◽  
Control Group ◽  
To Receive

Abstract The role of ursodeoxycholic acid (UDCA) in the prevention of hepatic complications after allogeneic stem cell transplantation was studied in a prospective randomized open-label multicenter trial. A total of 242 patients were allocated to receive (n = 123) or not to receive (n = 119) UDCA in the dose of 12 mg/kg/d orally from the day preceding the conditioning until day 90 after transplantation. In the UDCA-treated group a significantly smaller proportion of patients developed a serum bilirubin level exceeding 50 μM (18 of 123 versus 31 of 119, P = .04), and similarly a smaller proportion of patients exceeded the alanine aminotransferase level of 100 U/L. There was no difference in the incidence of veno-occlusive disease of the liver. Compared to the control group, in the UDCA-treated group there was a nonsignificant trend toward a lower overall incidence of acute graft-versus-host disease (GVHD) and a significantly lower incidence of grade III to IV acute GVHD (5 of 123 versus 17 of 119,P = .01), stage II to IV liver and intestinal GVHD, and stage III to IV skin GVHD. There was no difference in the incidence of chronic GVHD or in the relapse rate. Among the patients given UDCA, the survival at 1 year was significantly better, 71% versus 55% (P = .02), and the nonrelapse mortality rate was lower, 19% versus 34% (P = .01), than in the control group. There were significantly more deaths in GVHD in the control group. In conclusion, UDCA administration reduced hepatic problems and severe acute GVHD and improved survival. These results suggest a role for UDCA in the prevention of transplant-related complications in allogeneic transplantation.

Hyperlipidemia After Allogeneic Stem Cell Transplantation: Prevalence, Risk Factors and Impact on Prognosis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3458-3458
Author(s):  
Yuki Kagoya ◽  
Sachiko Seo ◽  
Yasuhito Nannya ◽  
Mineo Kurokawa
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Relapse Rate ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Calcineurin Inhibitors

Abstract Abstract 3458 Introduction: Hyperlipidemia is one of the late complications after allogeneic stem cell transplantation (SCT). Although intrahepatic cholestasis caused by chronic graft-versus host disease (GVHD) or calcineurin inhibitors has been considered to be one of the etiologies, its prevalence, risk factors, and the impact on prognosis have not been investigated well. Methods: We performed a retrospective analysis of 194 adult patients who underwent allogeneic SCT between 1995 and 2008 in our institute, and survived more than 100 days after SCT. Hypercholesterolemia or hypertriglyceridemia was defined as more than 240 mg/dl or 200 mg/dl, respectively, at two successive tests at least one week apart after the first 100 days after SCT. Cumulative incidence of hypercholesterolemia or hypertriglyceridemia was analyzed. The time to the development of hypercholesterolemia or hypertriglyceridemia was calculated and the multivariate analysis of pre- and posttransplant variables was performed by a Cox proportional hazards model. Chonic GVHD, chronic liver dysfunction (CLD; defined as more than twice the upper limit of normal for aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase, or total bilirubin >3 mg/dl over 3 months) and administration of calcineurin inhibitors were studied as posttransplant factors, which were assessed as time-dependent variables. To analyze the prognosis of patients who developed persistent hyperlipidemia, the multivariate analysis of overall survival (OS), relapse rate, and non-relapse mortality (NRM) was carried out by a landmark approach. Persistent hyperlipidemia was defined as hypercholesterolemia or hypertriglyceridemia continuing more than 3 months. Results: Overall, 83 (42.8%) and 98 (50.5%) patients developed hypercholesterolemia and hypertriglyceridemia, respectively. The median follow-up period of serum cholesterol and triglyceride values in surviving patients was 44 months. The cumulative incidence of each abnormality at 3 years after SCT was 38.1% (95% confidence interval [CI]: 31.0–45.1%), and 46.0% (95% CI: 38.8–52.9%), respectively. In a multivariate analysis, the development of chronic GVHD was independently associated with both hypercholesterolemia (hazard ratio [HR] 2.05, 95% CI: 1.23–3.43, P<0.01) and hypertriglyceridemia (HR 2.04, 95% CI: 1.30–3.18, P<0.01). Besides, CLD was significantly associated with hypercholesterolemia (HR 2.20, 95% CI: 1.39–2.50, P<0.01). Administration of calcineurin inhibitors was not an independent risk factor for the development of hypercholesterolemia (HR 1.23, 95% CI: 0.73–2.08, P=0.43) or hypertriglyceridemia (HR 1.03, 95% CI: 0.61–1.54, P=0.89). Among pretransplant factors, prior hypercholesterolemia and hypertriglyceridemia were associated with posttransplant hypercholesterolemia (HR 2.76, 95% CI: 1.07–7.17, P=0.04) and hypertriglyceridemia (HR 2.04, 95% CI: 1.27–3.27, P<0.01), respectively. Persistent hyperlipidemia was found in 49 patients (25.3%), of which 35 patients (71.4%) developed hyperlipidemia within one year. The median interval to the occurrence of hyperlipidemia of the patients was 180 days after SCT. In univariate analysis, patients with persistent hyperlipidemia had a tendency of better 3-year OS (77.3% vs 64.7%, P=0.23). Multivariate analysis showed that the development of persistent hyperlipidemia was independently associated with better OS (HR: 0.49, P=0.049). Further, although not statistically significant, patients with persistent hyperlipidemia had a tendency of lower 3-year cumulative relapse rate (15.7% vs 20.3%). There were no significant differences in 3-year NRM between patients with or without hyperlipidemia (12.3% vs 13.9%). Conclusions: Both hypercholesterolemia and hypertriglyceridemia are very common complications after SCT. Patients with persistent hyperlipidemia, however, have significantly better OS. Considering a strong association between the development of hyperlipidemia and chronic GVHD, and a tendency of lower relapse rate in patients with persistent hyperlipidemia, hyperlipidemia is regarded as one of the symptoms accompanied with chronic GVHD. Unless severe, its incidence indicates a better control of the primary disease and an improved prognosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Age on Hospitalization and Readmission on Post Allogeneic Stem Cell Transplantation Outcome, Single Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4122-4122
Author(s):  
Eshrak Al-Shaibani ◽  
Shiyi Chen ◽  
Wilson Lam ◽  
Arjun Law ◽  
Ivan Pasic ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hospitalization Period

Abstract Background: Recent advances and improvement of supportive care allowed allogeneic stem cell transplantation (HCT) to be offered to selected older patients. However, data regarding outcome and factors affecting the outcomes are limited. Method: We retrospective analyzed the outcome in 332 patients, median age 65 years (60-76), who underwent HLA-matched related (n=85), matched unrelated (n=205) and haploidentical donor (n=42) HCT, between January 2014 to December 2019. Of these 60% were male. Diagnosis was leukemia: 193, MDS: 76, MF: 46 and others: 17. Graft source was PBSC in 98%. Reduce-intensity conditioning regimen was used in 95%, and in vivo T-cell depleted in 89% of patients. We categorized them to 3 age-groups (G): G1 60-65y, (n=175), G2 &gt;65-70y (n=127), and G3 &gt;70y (n=30).Cox models were used to compare the rates of overall survival (OS), non-relapse mortality( NRM), event free-survival (EFS), length of hospitalization for HCT, GVHD and reasons of re-hospitalization during the first year post HCT. Results: The median follow up was 14 months (range: 1-123 months). Median days of hospitalization during HCT period were 30-days (range: 20-132 days), with trend towards significance when stratified by age group (p=0.049). HCT-CI scores were 0-1 (n=143), 2-3 (n=107) and &gt;3 (n=70). The cumulative incidences of grade II-IV acute-GVHD was 38.3% and 16.3% for grades III-IV. Moderate-severe chronic-GVHD was 23.7%. Increasing age was not associated with increases in acute GVHD (p=0.86) or chronic-GVHD (p= 0.6). Overall, 188 (56%) patients were re-hospitalized within the first 6-month of HCT, and 61 (18%) in the second 6-month period. The 2-year OS rate (Fig 1) were 56% in G1, 53% in G2 and 34% in G3 (p=0.05). The 2-year EFS rate (Fig 2) were 54% for G1, 49% for G2, and 31% for G3 (P=0.04). Cumulative incidence of NRM at 2-year (Fig 3) were 25% in G1, 36% in G2 and 52% in G3 (p=0.008). Further results are illustrated in Table 1. Risk factors such as age, KPS, HCT-CI, donor-type, readmission and GVHD were analyzed for their associations with outcomes using univariate analyses, those with significant results entered in multivariate-analysis Table 2. Patients aged 60-≤65 had significantly better EFS (p=0.04) and associated with a border line significant trend for lower NRM (p=0.05) than those aged &gt;70. Re-admission in the first 6-month post HCT had a significant impact on the OS, EFS and NRM. HCT-CI &gt;3 had significant impact on NRM. Conclusion: Age had a significant impact on hospitalization period during HCT. Age &gt;70 had significant impact on EFS and trend toward higher NRM. HCT-CI, acute and chronic-GVHD and readmission in first 6-month post-HCT were significant risk factors. Readmission in the first 6 months correlated with lower OS, EFS and higher NRM. Acute GVHD III-IV or moderate-severe chronic GVHD associated with poor outcomes. Selecting patients based on HCT-CI, and good management of GVHD and post-HCT complication may improve the clinical outcome. Figure 1 Figure 1. Disclosures Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Kim: Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria; Paladin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding.

Incidence, Risk Factors and Outcomes of Bronchiolitis Obliterans after Allogeneic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3365-3365
Author(s):  
Chiaki Nakaseko ◽  
Shinnichi Ozawa ◽  
Miki Nishimura ◽  
Miwa Sakai ◽  
Kumi Ohshima ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Respiratory Failure ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Bronchiolitis Obliterans ◽  
Chronic Gvhd ◽  
Time Interval

Abstract Background: Bronchiolitis obliterans (BO) after allogeneic stem cell transplantation (allo-SCT) is a late-onset, life-threatening respiratory complication which significantly reduces patients’ quality of life. Despite different therapeutic protocols, BO mortality remains high and most patients die of respiratory failure or infections. In recent practice, the source of stem cells and the conditioning regimen for allo-SCT have become more varied, but their influence on the incidence of BO is not established. Here, we retrospectively analyzed incidence of and risk factors for BO in allo-SCT protocols. Patients and methods: Between Jan 1994 and June 2005, 2692 patients underwent allo-SCT in 14 facilities of the Kanto Study Group for Cell Therapy (KSGCT) in Japan, and 2154 surviving at least 100 days after transplantation were evaluated in this study. Clinical diagnosis of BO was made by pulmonary function tests (PFT) revealing a forced expiratory volume for 1 second (FEV1) less than 70% and FEV1/forced vital capacity less than 80% of the predicted value, along with typical changes on high-resolution computed tomography. Results: BO developed in 57 patients with a cumulative incidence at 5 years post transplant of 2.6%. The Kaplan Meier estimate of median time interval from transplant to diagnosis of BO was 335 days (83–907). The cumulative incidence of BO at 5 years was 1.62% (12/691) in bone marrow transplants from related donors (R-BMT), 3.83% (16/424) in peripheral blood stem cell transplantation from related donors (R-PBSCT), 2.91% (24/808) in BMT from unrelated donors (UR-BMT), and 2.65% (5/199) in unrelated cord blood transplantation (CBT). The incidence of BO after R-PBSCT was significantly higher than after any other type of allo-SCT (p=0.02). At BO diagnosis, the mean value of FEV1% decreased to 52.1% from 82.2% pre-transplant. 94% of patients had already developed chronic GVHD before the onset of BO. Risk factors for BO by univariate analysis were R-PBSCT (p=0.019) and preceding chronic GVHD (p=0.000). Twenty eight patients died after developing BO, 21 of respiratory failure. Only one patient died of relapse of primary disease. Overall 5 yr-survival of patients with BO from the time of diagnosis was 46.5%, significantly less than for those without (76.2% from day 335, p=0.000) by semi-landmark analysis. Conclusions: The incidence of BO in CBT recipients was higher than R-BMT recipients and not significantly different with UR-BMT recipients. R-PBSCT recipients who have already developed chronic GVHD have a higher risk for developing BO and need extensive care and repeated PFT examinations.

scholarly journals Alemtuzumab As Pre-Conditioning Is Safe and Feasible in Patients with T-Cell Lymphoid Neoplasms Undergoing Allogeneic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5863-5863
Author(s):  
Sara Lozano ◽  
Amaya Zabalza ◽  
Intza Aoiz ◽  
Mohamed Hamdi Djatri ◽  
Pedro Arregui ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cell Lymphoma ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity

Abstract Background: In vivo T-cell depletion with Alemtuzumab reduces the incidence of acute and chronic graft-versus-host disease (GvHD) and graft failure, yet it results in an increase of opportunistic infections and delayed immune recovery. In addition, Alemtuzumab has considerable anti-lymphoma activity in T-cell neoplasms. We report on a pilot study analysing the safety and feasibility of Alemtuzumab as pre-conditioning prior to reduced intensity conditioning allogeneic stem cell transplantation (RIC-alloSCT) in patients diagnosed with T-cell non-Hodgkin lymphoma. Methods: Six consecutive patients diagnosed with a T-cell lymphoid malignancy underwent RIC-alloSCT from a HLA-identical sibling (n=5) or a matched unrelated donor (n=1). Diagnosis were Angioimmunoblastic T-cell lymphoma (n=3), hepato-splenic gamma-delta T-cell lymphoma (n=1), T/NK cavum lymphoma (n=2) and Sèzary Syndrome (n=1). All received unmanipulated peripheral blood stem cells; At transplantation 2 patients were in CR, and 4 in PR. Median number of prior regimens was 2 (range 2-5). Conditioning regimen included Fludarabine (5 x 30mg/m2) and Melphalan (2 x 70mg/m2) in all cases. GvHD prophylaxis comprised Cyclosporine A and Methotrexate. The pre-conditioning protocol consisted on 6 escalating doses of intravenous Alemtuzumab starting on day -28 (3 mg on day -28, 10 mg on day -26 followed by four doses of 30 mg on days -24 to -17) given 3 times a week (MWF) on an out-patient basis. Results: Five patients received all six doses of Alemtuzumab as planned whereas one patient received only four doses for logistic reasons related to donor availability. Acetaminophen, Hydrocortisone and Dexchlorpheniramine were administered as pre-medication in all cases with no severe infusional reaction observed. There were no delays in proceeding to SCT conditioning and patients develop no infectious complications during the Alemtuzumab - alloSCT interval. All patients engrafted with a median time to neutrophil engraftment of 23 days (range 14-27). Acute skin GvHD (grade I and III) was observed in 2 patients (33.3%), both obtaining a CR with topical and systemic corticosteroids respectively. Two patients developed mild ocular chronic GvHD (one after subsequent infusions of donor lymphocytes - DLI) but none has suffered from extensive chronic GvHD. No opportunistic infection was observed apart from CMV reactivation that developed in 3 out of 4 seropositive patients (no CMV disease was observed). All patients experienced delayed immune reconstitution (CD4 >200/ul) at a median of 321 days (range 229-518). All 4 patients in PR prior to alloSCT achieved a complete remission. Only one patient (diagnosed with Sèzary Syndrome) experienced a relapsed and responded to DLI. With a median follow-up of 42 months, all patients remain alive and in CR. Conclusions: Our preliminary results suggest that administration of Alemtuzumab prior to reduced intensity conditioning is feasible and safe. In addition to providing T-cell depletion, Alemtuzumab may improve the response rate in T-cell lymphoid malignancies without increasing the risk of infectious complications. These results require further validation in larger phase II studies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

NOD2/CARD15 Variants of Donor and Recipient as Critical Risk Factors for the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 144-144
Author(s):  
Gerhard Hildebrandt ◽  
Daniel Wolff ◽  
Bernd Hertenstein ◽  
Hildegard T. Greinix ◽  
Gerhard Rogler ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Bronchiolitis Obliterans ◽  
Chronic Gvhd ◽  
Bronchiolitis Obliterans Syndrome ◽  
Bronchial Epithelial

Abstract Bronchiolitis obliterans syndrome (BOS) is a life-threatening complication after allogeneic stem cell transplantation (SCT), that affects primarily small airways. BOS mortality is high and risk factors and pathophysiology have yet to be defined. Experimental data from BOS in heterotopic traecha transplant models suggest, that both bronchial epithelial cell (EC) integrity as well as an alloantigen-reactive T cell response are involved. We recently reported an association of single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene resulting in a diminished NF- κB response to bacterial cell wall products with increased acute graft versus host disease (GVHD) severity and transplant-related mortality. As NOD2/CARD15 is expressed not only in monocytes/macrophages and intestinal EC but also in bronchial EC, we hypothesized that NOD2/CARD15 variants contribute to changes in host defense and alloreaction leading to BOS. We analyzed the association of NOD2/CARD15 SNPs (SNP 8, 12, 13) with the occurrence of BOS within 244 donor/recipient (D/R) pairs of patients (pts) receiving allogeneic SCT. Follow-up was performed for a mean of 1243±172 days (range: 327–2149). BOS was diagnosed by pathology or by functional airway obstruction (FEV1&lt;/= 80% of predicted). 12 pts developed BOS with a mean time point of diagnosis at 678±112 days after SCT (range: 186–1407). Incidence of BOS rose from 1.7% (3/174) in D/R pairs without mutated SNPs to 10.0% (6/60) in pairs with mutated alleles in either donor or recipient (p=0.01) and to 25.0% (3/12) in pairs with mutated alleles in both donor and recipient (p=0.009). In addition, in D/R pairs developing BOS, NOD2/CARD15 variants were observed at higher frequencies (donor: 60.0% vs. 12.9%, p=0.001; recipient: 50.0% vs. 15.0%; p=0.007). 50% of pts with BOS died between day +327 and day +1582 (mean: 844±195), whereas 6 pts are still alive (mean follow-up: 1642±170 days). Survival did not differ between pts with BOS in relation to the presence/absence of NOD2/CARD15 mutations. Finally, we analyzed whether other transplant-related parameters contributed to the incidence of BOS. Conditioning regimen intensity, stem cell source, donor type (matched unrelated donor vs. HLA-identical sibling), recipient age, donor or recipient gender, and acute GVHD were not associated with BOS development, whereas chronic GVHD was confirmed as a risk factor for BOS (p=0.01). Interestingly, NOD2/CARD15 mutations did not associate with chronic GVHD (p=0.19). Our data indicate that NOD2/CARD15 mutations of donor or recipient increase the risk of developing BOS after allogeneic SCT, which may be due to impaired macrophage function, to impaired defence mechanisms of bronchial epithelial cells, or to other pathways still unknown. Further, future risk assessment before SCT using NOD2/CARD15 typing may help identifying patients at higher risk for BOS and improve clinical outcome after allogeneic SCT.

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