Woo-Sung Min

Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation.

Background. The lack of an accepted definition of transplantation-associated thrombotic microangiopathy (TMA) has led the Blood and Marrow Transplants Clinical Trials Network (CTN) and International Working Group (IWG) to propose a definition for TMA with some differences. However, there have been few studies validating and comparing both newly proposed criteria for TMA. Methods. To validate recently proposed criteria for TMA by CTN and IWG, we analyzed 672 patients who underwent allogeneic stem-cell transplantation between January 2002 and December 2006. Results. The cumulative incidences of TMA by CTN and IWG were 6.1% and 2.5%, respectively. The cumulative incidence of overall TMA (O-TMA) including probable-TMA defined as meeting CTN criteria without renal or neurologic dysfunction, as well as TMA by CTN (definite-TMA), was 12.7%. Sixty-six percent of TMA by CTN did not have any degree of schistocytosis by IWG criteria (≥4%), and 18% of TMA by IWG criteria did not have renal or neurologic dysfunction. On multivariate analyses, probable-TMA as well as definite-TMA adversely affected the survival of a cohort including all patients. In patients with O-TMA, the degree of schistocytosis (≥4% or not) failed to show prognostic significance, whereas renal involvement was a significant prognostic factor associated with poor survival. Conclusions. Both proposed consensus criteria have major pitfalls in their use as uniformly accepted diagnostic criteria for TMA. The use of O-TMA as a broad definition for TMA and the grading system by the presence of renal involvement may be a counterproposal for future trials.

Feasibility of NIH consensus criteria for chronic graft-versus-host disease

To assess the applicability of the National Institutes of Health (NIH) consensus criteria (NCC) for chronic graft-versus-host disease (cGVHD), 211 patients who developed GVHD more than 100 days after allogeneic transplantation were reclassified using NCC. Classifications were: late acute GVHD (44 patients, 21%), overlap syndrome (64 patients, 30%) and classic cGVHD (103 patients, 49%). Classic cGVHD and overlap syndrome patients (n=167) were graded using both the revised Seattle criteria (RSC) and NIH global scoring (NGS). Twenty-three patients (14%) had mild, 81 (48%) had moderate and 63 (38%) had severe cGVHD. After a median follow-up of 46 months (range 5–71 months), the 4-year GVHD-specific survival was not significantly different among the different subtypes of NCC. Among patients with late acute GVHD, however, the pattern of acute GVHD onset (late, persistent or recurrent) was significantly different with respect to GVHD-specific survival. Among patients with overlap syndrome and classic cGVHD, multivariate analysis showed that NGS as well as RSC were useful in predicting survival and discontinuation of immunosuppressive therapy despite of more detailed grouping. Our study indicates that NCC is applicable. The clinical impact of NIH types and NGS should be verified through prospective studies.

The kinetics of circulating cytokines including IL-6, TNF-α, IL-8 and IL-10 following allogeneic hematopoietic stem cell transplantation

Pro-inflammatory (IL-6, TNFα and IL-8) and anti-inflammatory (IL-10) cytokines were determined in weekly samples from 52 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). IL-6 increased immediately after transplant peaking at week +3, but IL-8 concentrations were elevated only during week +1. After a slight decrease in week +1, TNF-α significantly increased from week +2 and peaked at week +3, whereas, IL-10 values started to rise in week +2 and peaked during week +4. IL-6 and TNF-α were positively correlated from week +2 to week +4, and IL-6 levels at week +1 were related with fever and severe stomatitis. Serum levels of IL-6 at week +1 and IL-10 at week +4 were significantly higher in patients with early transplant-related complications, such as fever, severe stomatitis or acute GVHD ⩾ overall grade II than in those without the complications. We conclude that a high serum IL-6 level at week +1 may be an early predictor of transplant-related complications and that it seems to trigger pro- and anti-inflammatory cytokine release. Kinetic patterns of IL-6 and IL-10 were more exaggerated in those with complications after HSCT. Bone Marrow Transplantation (2001) 28, 935–940.

Liver disease during the first post-transplant year in bone marrow transplantation recipients: retrospective study.

Liver dysfunction is a common problem in BMT recipients and it is important to determine the etiology in order to institute appropriate therapy. The purpose of this study was to evaluate the possible causes of liver dysfunction during the first post-transplant year in BMT recipients and to identify a possible relationship between pre-existing liver dysfunction and viral hepatitis with prognosis after BMT. We reviewed liver status before and after BMT in 130 consecutive patients at the Catholic Hematopoietic Stem Cell Transplantation Center. Liver dysfunction during the first post-transplant year occurred in 85 out of 101 (84.2%) allogeneic BMT recipients and 13 out of 29 (44.8%) autologous BMT recipients. In allogeneic BMT, GVHD and drug hepatotoxicity were major causes. In autologous BMT, drug hepatotoxicity was the most common cause. Eighteen out of 130 patients (13.8%) had abnormal liver function tests before BMT. These patients did not have an increased risk of post-transplant liver dysfunction, GVHD, and death compared to patients who had normal liver function tests prior to BMT. Nine patients were hepatitis B antigen positive and three patients were anti-HCV positive prior to BMT. There was no significant increase in the incidence of post-transplant liver dysfunction, GVHD, and death in these patients. Bone Marrow Transplantation (2000) 26, 193–197.

Vascular endothelial growth factor (VEGF) is associated with reduced severity of acute graft-versus-host disease and nonrelapse mortality after allogeneic stem cell transplantation

This study investigated whether or not there is a correlation between the changes in the serum levels of vascular endothelial growth factor (VEGF) and the outcome of allogeneic stem cell transplantation (allo-SCT). Eighty-five patients undergoing allo-SCT were prospectively studied. The serum VEGF levels were measured on days 0, +7 and +14 after transplantation. The VEGF levels decreased significantly on day +7 and recovered on day +14. The highest levels from day +7 through day +14 were categorized by cluster analysis, which were then correlated with the nonrelapse mortality (NRM). There was a significant correlation between a low VEGF level and the occurrence of severe acute graft-versus-host disease (GVHD) including grade III–IV (P=0.029). The 1-year probability of NRM in patients with a low VEGF level was 22.5% compared with 3.5% for those with a high VEGF level (P=0.024). Multivariate analysis revealed clinically defined infections (P=0.011), advanced disease (P=0.014) and a low VEGF cluster (P=0.05) to be significantly associated with the occurrence of NRM in the cohort. In conclusion, low VEGF levels after allo-SCT are associated with NRM with an exacerbated severity of acute GVHD. VEGF monitoring after a transplant might identify those patients at risk of severe transplant-related mortality.

Application of Nucleic Acid Sequence–Based Amplification for Diagnosis of and Monitoring the Clinical Course of Invasive Aspergillosis in Patients with Hematologic Diseases

BACKGROUND AND METHODS We evaluated nucleic acid sequence-based amplification (NASBA) and a galactomannan enzyme immunosorbent assay (GM-EIA) for the diagnosis of invasive aspergillosis (IA) in neutropenic febrile patients and for monitoring of its clinical course and outcome. Blood samples were collected twice per week from 128 patients with hematologic diseases during periods of neutropenic fever after undergoing chemotherapy or hematopoietic stem cell transplantation. A total of 448 blood samples were tested. RESULTS There were 14 patients with IA (2 patients with proven IA and 12 with probable IA). The median index of the initial NASBA in the IA group was more than 10-fold higher than that in the non-IA group. Galactomannan antigenemia (index, >0.5) was detected with a sensitivity of 86%. In receiver-operator characteristic analysis, the cutoff index of NASBA for the presumptive diagnosis of IA was determined to be 5.0. Combination of these 2 parameters (either a GM-EIA index of >or=0.5 or a NASBA index of >or=5.0) improved the sensitivity of diagnosis to 100%. There was a close relationship between patient outcome and the kinetics of NASBA values: failure of negative conversion during treatment resulted in death in almost all cases. CONCLUSION If either GM-EIA or NASBA results suggest IA, the diagnostic yield for IA could be improved, and NASBA could be a useful marker for predicting the clinical course and outcome of treatment.

Successful Prevention of Acute Graft-versus-Host Disease Using Low-Dose Antithymocyte Globulin after Mismatched, Unrelated, Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia

In this study, we investigated the effects of low-dose antithymocyte globulin (ATG, thymoglobulin) in the prevention of acute graft-versus-host disease (aGVHD) in mismatched, unrelated hematopoietic stem cell transplantations (uHSCTs) in patients with the single disease entity of acute myelogenous leukemia (AML). Patients (n = 103) with a variable risk for AML who received uHSCTs from available Asian and Caucasian donors were enrolled. First, we compared HLA-matched (group 1, n = 54) and HLA-mismatched (group 2, n = 49) transplantation patients. Then, we divided the patients in group 2, who had received transplants from allele(s)/antigen-mismatched donors, into 2 subgroups: patients who used ATG (group 3, n = 24) and those who did not (group 4, n = 25). To prevent the development of aGVHD, the patients in group 3 received ATG at a dose of 1.25 mg/kg body weight per day for 2 consecutive days, together with our standard regimen of methotrexate (MTX) and tacrolimus. The median CD34(+) cell infusion was 4.2 x 10(6)/kg (range: 1.2-34.4). The median patient age was 41 years (range: 16-57), and the median follow-up duration of patients who were event-free survivors was 23 months (range: 2-72). The overall incidences of aGVHD and chronic GVHD (cGVHD) were 38% and 56%, respectively. Of 48 evaluable patients in group 2, 10 (21%) developed moderate to severe aGVHD (grades II-IV). In contrast, 2 (8%) of the 24 patients in group 3 and 7 (29%) of the 24 evaluated patients in group 4 required therapy for aGVHD (grades II-IV; P = .038). The incidence of cGVHD was not different between groups 3 and 4. The estimated probabilities of overall survival (OS) and event-free survival (EFS) at 2 years for group 2 were 55% and 44%, respectively. In comparison, the estimated probabilities of OS and EFS at 2 years for groups 3 and 4 were 68% versus 38% (P = .043) and 58% versus 38% (P = .103), respectively. The overall cumulative incidence of nonrelapse mortality (NRM) was 29% in group 2. The cumulative incidence of NRM differed markedly between group 3 (16%; 95% confidence interval [CI], 4%-28%) and group 4 (44%, 95% CI, 34%-54%) (P = .013). We found no difference in cytomegalovirus (CMV) reactivation between groups 3 and 4. These results suggest that in mismatched uHSCT, a low dose of ATG (total 2.5 mg/kg) may prevent moderate to severe aGVHD, with comparable rates of relapse and CMV reactivation and a greatly decreased rate of NRM.

Infectious complications and outcomes after allogeneic hematopoietic stem cell transplantation in Korea

Summary:We reviewed 242 allogeneic hematopoietic stem cell transplantation (HSCT) recipients retrospectively over a 2-year period (January 1998–December 1999) in order to analyze the characteristics and assess the outcomes of infectious complications in patients after HSCT in Korea. Bacteria were the major pathogens before engraftment, and viral and fungal infections predominated during the post-engraftment period. Varicella zoster virus was the most common viral pathogen after engraftment. Cytomegalovirus disease occurred mainly in the late-recovery phase. The frequency of mold infection was higher than that of yeast. There was a relatively high incidence of tuberculosis (3.0%) and Pneumocystis carinii pneumonia (6.5%). One case of death by measles confirmed by autopsy was also noted. Overall, cumulative mortality was 43% (104/242), and 59.6% of these deaths (62/104) were infection-related. Allogeneic HSCT recipents from unrelated donors were prone to infectious complication and higher mortality than those from matched sibling (17/39 (43.6%) vs 45/203 (22.2%), respectively; P<0.01; odd ratio 2.5; 95% confidence interval 1.2–5.1). As infection was the main post-HSCT complication in our data, more attention should be given to the management of infections in HSCT recipients.

Reduced-intensity conditioning allogeneic stem cell transplantation is a potential therapeutic approach for adults with high-risk acute lymphoblastic leukemia in remission: results of a prospective phase 2 study

The aim of this prospective study was to investigate the feasibility of reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT) in 37 adults with high-risk acute lymphoblastic leukemia (ALL) in first (n=30) or second (n=7) complete remission (CR). All patients were treated with fludarabine (150 mg/m2) and melphalan (140 mg/m2) followed by transplantation from matched sibling (n=27) or unrelated (n=10) donors. The indications for reduced-intensity conditioning allogeneic SCT (RIC-SCT) were as follows: (1) ⩾50 years, 16 (43.2%) and (2) decreased organ function or active infections, 21 (56.8%). Graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitor (cyclosporine for sibling and tacrolimus for unrelated transplants) and methotrexate. The cumulative incidence of acute (grades II–IV) and chronic GVHD was 43.2 and 65.6%, respectively. After a median follow-up of 36 months for surviving transplants, the 3-year relapse, non-relapse mortality, disease-free survival and overall survival rates were 19.7, 17.7, 62.6 and 64.1%, respectively. Transplants in first CR showed better transplantation outcomes than those in second CR. The potential of antileukemic activity of chronic GVHD was also found. This study suggests that RIC-SCT is a potential therapeutic approach for adults with high-risk ALL in remission who are ineligible for myeloablative transplantation.

Cutaneous leucoclastic vasculitis (LV) following bortezomib therapy in a myeloma patient; association with pro-inflammatory cytokines.

Abstract:  The proteasome inhibitor, bortezomib, has anti‐myeloma activity even in myeloma cells refractory to multiple prior treatments. Bortezomib blocks the production of nuclear factor‐κB (NFκB)‐mediated pro‐inflammatory cytokines. We report a patient with myeloma who developed a cutaneous leucoclastic vasculitis (LV) after bortezomib treatment. The patient with LV exhibited a marked increase in serum levels of IL‐6, TNF‐α, and C‐reactive protein (CRP). Bortezomib administration may enhance the release of pro‐inflammatory cytokines, which might play a role in bortezomib‐induced cutaneous LV.