R M Y Barge

Infectious Complications of Central Venous Catheters Increase the Risk of Catheter-Related Thrombosis in Hematology Patients: A Prospective Study

PURPOSE We studied whether the risk of central venous catheter (CVC) -related thrombosis increased after an episode of CVC-related infection in patients undergoing intensive chemotherapy. Secondly, we determined whether thrombosis can be predicted or excluded by CVC lock fluid surveillance cultures. PATIENTS AND METHODS In a prospective setting, 105 consecutive patients were carefully examined for CVC-related infection and thrombosis. In all patients, microbial surveillance cultures of CVC lock fluid were taken every other day. All patients with clinical suspicion of CVC-related thrombosis underwent Doppler ultrasound or additional venography. RESULTS The cumulative incidence of CVC-related infection was 24% (25 of 105 patients). Clinically manifest thrombosis occurred in 13 (12%) of 105 patients. In patients with CVC-related infection, the risk of thrombosis increased markedly in comparison to those without infection (relative risk, 17.6; 95% CI, 4.1 to 74.1). In patients having two or more positive subsequent CVC lock fluid cultures with identical micro-organisms, 71.4% developed thrombosis, as compared with 3.3% in patients with negative or a single positive culture. CONCLUSION The risk of clinically manifest thrombosis is increased after an episode of CVC-related infection in patients undergoing intensive chemotherapy. Surveillance culturing of CVC lock fluid may be clinically useful in estimating the risk for thrombosis and the instigation of focused early intervention.

Partially T-Cell–Depleted Allogeneic Stem-Cell Transplantation for First-Line Treatment of Multiple Myeloma: A Prospective Evaluation of Patients Treated in the Phase III Study HOVON 24 MM

PURPOSE To determine in a prospective study the efficacy, toxicity, and long-term outcome of up-front allogeneic stem-cell transplantation (allo-SCT) in multiple myeloma (MM). PATIENTS AND METHODS In the prospective phase III study by the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON), HOVON 24 MM, 53 patients with an HLA-identical sibling (median age at transplantation, 48 years; range, 31 to 56 years) were allocated to a partial T-cell-depleted allo-SCT after induction therapy. RESULTS The overall response rate after allo-SCT was 89% (47 of 53 patients), including the 19% of patients (10 of 53 patients) with a complete remission (CR). Five patients achieved a CR only after allo-SCT. Five (71%) of seven primary refractory patients obtained a response to allo-SCT, all of whom had a partial remission. With a median follow-up of 38 months (range, 25 to 61 months), 20 patients are alive since allo-SCT and 33 patients have died (14 from progressive disease, 18 from treatment-related mortality [TRM], and one from another cause). Occurrence of acute graft-versus-host disease grades 2 to 4 predicted for higher TRM in a time-dependent analysis. The median progression-free survival time after allo-SCT was 17 months. Median overall survival time after allo-SCT was 25 months, or 29 months from the start of therapy. Only three patients are in continuing CR, indicating that the potential cure rate of this approach is, at best, 6%. CONCLUSION This first prospective evaluation of up-front allo-SCT of MM in a multicenter setting does not support the use of T-cell-depleted myeloablative allo-SCT as part of first-line therapy.

High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: Results of an open study to assess feasibility, safety, and efficacy

OBJECTIVE To assess the feasibility, safety, and efficacy of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in patients with severe, refractory rheumatoid arthritis (RA). METHODS Fourteen patients (3 male, 11 female, mean age 43 years, mean disease duration 10 years) with active, destructive, refractory RA entered the study. Autologous hematopoietic stem cells were collected by leukapheresis after mobilization with a single infusion of cyclophosphamide (CYC; 4 gm/m2) and subcutaneous injections of filgrastim (granulocyte colony-stimulating factor). Immunomagnetic selection of CD34+ cells from the leukapheresis products was performed to deplete potentially autoreactive lymphocytes. The conditioning regimen consisted of intravenous administration of high doses of CYC (cumulative dose 200 mg/kg), with subsequent reinfusion of the graft. Patients were monitored for disease activity, disability, adverse effects, and hematopoietic and immunologic reconstitution. RESULTS All 14 patients completed the mobilization and leukapheresis procedures successfully, and 12 proceeded to receive conditioning and transplantation. Engraftment occurred in all of these patients, with rapid hematologic recovery. No major unexpected toxicity was observed. Marked improvement of disease activity was recorded in 8 of 12 patients at >50% of the visits, with a followup ranging from 7 months to 21 months. The clinical responders included 2 patients who had previously failed treatment with tumor necrosis factor (TNF) blocking agents. CONCLUSION High-dose chemotherapy followed by autologous HSCT is feasible and safe, and can result in long-term improvement of disease activity in patients whose condition previously did not respond to conventional antirheumatic drugs or TNF blocking agents. The persistence of active disease in some patients may reflect the heterogeneity of the underlying disease process.

Central venous catheter related thrombosis in haematology patients and prediction of risk by screening with Doppler-ultrasound.

Summary. Patients with a central venous catheter (CVC) who receive intensive chemotherapy or a stem cell transplantation for haematological disease are at risk for developing CVC‐related thrombosis. To study the incidence of thrombosis, 105 consecutive patients underwent serial Doppler‐ultrasound and we evaluated whether clinically manifest thrombosis could be predicted by screening with Doppler‐ultrasound. Patients with subclavian or jugular inserted CVCs were clinically assessed each day for signs and symptoms of thrombosis. Additional Doppler‐ultrasound screens were performed weekly by an independent physician in all patients until CVC removal. Doppler‐ultrasound recordings were assessed by two blinded observers. In cases of clinically suspected thrombosis, the attending physicians followed routine diagnostic and therapeutic procedures. The overall cumulative incidence of CVC‐related thrombosis was 28·6% (30 of 105 patients). Of the 30 patients with thrombosis, 26 had subclinical thrombosis by Doppler‐ultrasound, nine of whom developed clinically manifest thrombosis later. Four patients had clinically manifest thrombosis without prior abnormal Doppler‐ultrasound. In cases of subclinical thrombosis the risk of developing symptomatic disease increased sevenfold (34·6% vs. 5·1%). Doppler‐ultrasound screening may be useful to identify those patients that are at high and low risk for clinically manifest CVC‐related thrombosis.

Long-term follow-up of myeloablative allogeneic stem cell transplantation using Campath ‘in the bag’ as T-cell depletion: the Leiden experience

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic stem cell transplantation (alloSCT) but can be prevented by removing T-lymphocytes from the graft. Campath (anti-CD52) antibodies have been widely used in vivo for T-cell depletion following conventional and reduced intensity conditioning regimens. The use of Campath in vivo was associated with a significant reduction in GVHD but at the cost of impaired immune reconstitution. We evaluated the long-term outcome of 73 myeloablative allogeneic stem cell transplants with HLA-identical sibling donors using Campath ‘in the bag’ as method of in vitro T-cell depletion. All patients engrafted and hematopoietic recovery was uneventful, resulting in a median of 99% donor chimerism at 3 months after alloSCT. Cytomegalovirus (CMV) reactivation occurred in 53% of the patients. No CMV disease was observed probably as a result of pre-emptive (val)ganciclovir treatment. The incidence of aGVHD was low (22% grade II). No grades III–IV aGVHD was observed and extensive chronic GVHD (cGVHD) occurred in 19% of the patients. The low incidence of GVHD and successful pre-emptive antiviral therapy resulted in low TRM of 8%. Sixteen patients died due to disease relapse after alloSCT, resulting in an overall survival of 48% at 5-years after alloSCT.

Oral valganciclovir as pre-emptive therapy has similar efficacy on cytomegalovirus DNA load reduction as intravenous ganciclovir in allogeneic stem cell transplantation recipients.

The efficacy and safety of oral valganciclovir was compared to ganciclovir i.v. in pre-emptive treatment of cytomegalovirus (CMV) in T-cell-depleted allogeneic stem cell transplant (allo-SCT) recipients. A therapeutic guideline was developed to allow the safe application of valganciclovir in allo-SCT recipients requiring CMV therapy. In total, 107 consecutive transplant recipients were evaluated. Cytomegalovirus DNA load in plasma was monitored longitudinally; details on antiviral therapy and treatment responses were analyzed retrospectively. Fifty-seven CMV treatment episodes were recorded in 34 patients: 20 with valganciclovir (900 mg twice-daily) and 37 with ganciclovir (5 mg/kg twice-daily). Median CMV DNA load reduction was 0.079 and 0.069 log10 copies/ml/day in the ganciclovir and valganciclovir group, respectively. Good response on CMV DNA load (reduction below 3.0 log10 copies/ml) was observed in 75.7% of ganciclovir and 80.0% of valganciclovir treatment episodes. Severe adverse effects were not observed and CMV-related disease did not occur. However, the percentage of patients receiving erythrocyte transfusion was higher in the group of patients receiving ganciclovir as compared to valganciclovir (41 versus 20%, P=0.116). In conclusion, pre-emptive treatment with valganciclovir and ganciclovir, led to similar reduction of CMV DNA load. Oral valganciclovir is an attractive and safe alternative for pre-emptive CMV treatment in T-cell-depleted allo-SCT recipients.

Prevention of Coagulase-Negative Staphylococcal Central Venous Catheter–Related Infection Using Urokinase Rinses: A Randomized Double-Blind Controlled Trial in Patients With Hematologic Malignancies

PURPOSE Fibrin deposition at the intraluminal surface of the indwelling part of the central venous catheter (CVC) surface increases the risk of CVC-related coagulase-negative staphylococci (CoNS) infection. Therefore, repetitive enzymatic dissolution of fibrin by urokinase might reduce the risk of CVC-related infection. We undertook this study to investigate whether three times weekly urokinase rinsing of CVC reduces the incidence or severity of CVC-related infections by CoNS in patients undergoing intensive cytotoxic treatment for hematologic malignancies. PATIENTS AND METHODS In a double-blind setting, all consecutive patients with a CVC were randomly allocated to receive either urokinase rinses (5 mL of 5,000 U/mL) or placebo (saline), both three times weekly. RESULTS The percentage of patients with at least one positive culture with CoNS was lower in patients receiving urokinase compared with patients receiving placebo (26% v 42%, respectively; relative risk [RR] = 0.61; 95% CI, 0.39 to 0.94). Major CVC-related CoNS infection occurred less frequently in patients receiving urokinase versus placebo (1.2% v 14.1%, respectively; RR = 0.09; 95% CI, 0.01 to 0.50). Secondary complications, including CVC-related thrombosis, were observed less frequently in the urokinase group compared with the placebo group (1.3% v 9.0%, respectively; RR = 0.14; 95% CI, 0.02 to 0.82). No severe bleeding complications attributable to urokinase were observed. CONCLUSION Three times weekly urokinase rinsing reduces the incidence of CVC-related CoNS infection in patients treated with intensive cytotoxic therapy for hematologic malignancies, with acceptable safety.

Minimal GVHD following in-vitro Tcell–depleted allogeneic stem cell transplantation with reduced-intensity conditioning allowing subsequent infusions of donor lymphocytes in patients with hematological malignancies and solid tumors

OBJECTIVE Allogeneic stem cell transplantation (alloSCT) following reduced-intensity conditioning offers a relatively nontoxic regimen while preserving rapid and sustained engraftment. Acute and chronic graft-vs-host disease (GVHD) is, however, a significant cause of severe morbidity. To reduce the incidence of GVHD, we treated a group of high-risk patients with a reduced-intensity conditioning regimen followed by in vitro T-cell-depleted alloSCT using Campath 1-H incubation. PATIENTS AND METHODS Eighteen patients were treated with fludarabine (6 x 30 mg/m(2)), busulphan (2 x 3.2 mg/kg), and ATG (4 x 10 mg/kg) followed by the infusion of high-dose T-cell-depleted peripheral stem cells from sibling donors. No posttransplant GVHD prophylaxis was administered. At 6 months after alloSCT, low-dose donor lymphocyte infusion (DLI) was administered. RESULTS All patients had sustained engraftment of donor cells with a median of 95% donor cells at 3 months after alloSCT. Minimal acute and no chronic GVHD was observed after alloSCT. A high incidence of cytomegalovirus (CMV) reactivation but no CMV disease was observed. Eleven patients received DLI at a median of 6.5 months after alloSCT. Acute GVHD grade II-III developed in 6 patients. All patients showed improvement of donor chimerism after DLI. With a median follow-up of 211 days, 11 patients are alive. Particular in patients with chronic lymphocytic leukemia and acute myeloid leukemia, a significant graft-vs-tumor effect was observed. CONCLUSIONS In vitro T-cell-depleted alloSCT following reduced-intensity conditioning leads to durable donor engraftment without GVHD. The high levels of donor chimerism allow the subsequent use of cellular immunotherapy to treat residual disease.

Assessment of disseminated adenovirus infections using quantitative plasma PCR in adult allogeneic stem cell transplant recipients receiving reduced intensity or myeloablative conditioning.

Objectives:  Disseminated adenovirus (AdV) infections following allogeneic stem cell transplantation (allo‐SCT) are increasingly recognised, particularly in children. This study evaluated the clinical relevance of disseminated AdV infections in adult allo‐SCT recipients, after different conditioning regimens.

Expression of co-stimulatory and adhesion molecules and chemokine or apoptosis receptors on acute myeloid leukaemia : high CD40 and CD11a expression correlates with poor prognosis

The expression of adhesion and co‐stimulatory molecules, and chemokine and death receptors such as tumour necrosis factor (TNF) and FAS on acute myeloid leukaemia (AML) may influence the biology of the disease and response to chemotherapy and immunotherapy. In this study, we analysed the expression of these molecules in 99 AML patients using monoclonal antibodies and flow cytometry, and correlated the expression with French–American–British (FAB) classification and survival. The following molecules were studied: the co‐stimulatory molecules CD80, CD86 and CD40; the adhesion molecules CD11a‐c, CD31, CD43, CD50, CD54, CD102, CD58 and CD62L; the chemokine receptor CXCR4; and the death receptors TNFR1 and TNFR2 and FAS. The expression of all molecules was significantly higher in the M4/M5 FAB subgroups except for CD80, CD43, CD54 and CD62L. The AML M3 subgroup had a significant lower expression of CD11a (P = 0·02) and CD11c (P = 0·03). Five‐year survival was significantly shorter in cases of high CD40 expression [> 20% positive cells, relative risk (RR) 2·56, P = 0·02] or high CD11a expression (> 80% positive cells, RR 2·6, P = 0·03). This effect was most prominently present in the AML M4/M5 FAB subgroups. We conclude that the expression levels of adhesion and co‐stimulatory molecules, CXCR4 and apoptosis‐receptors are predominantly FAB subtype‐related with high CD40 and CD11a expression as poor prognostic factors.