Craig S. Rosenfeld

Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study

Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters.

Allogeneic blood cell transplantation without posttransplant colony-stimulating factors in patients with hematopoietic neoplasm: a phase II study.

PURPOSEnThere is limited experience with allogeneic blood cell transplantation (BCT). In an earlier pilot study, the combination of bone marrow and blood did not produce severe acute graft-versus-host disease (GVHD). We now report the results of a phase II study using blood stem cells alone in 19 patients.nnnPATIENTS AND METHODSnThe median age was 40 years. All patients had hematopoietic malignancies and received transplants from HLA-identical sibling donors. GVHD prophylaxis consisted of cyclosporine plus prednisone. Posttransplant colony-stimulating factors were not administered. Donors were mobilized with subcutaneous granulocyte colony-stimulating factor (G-CSF; 16 microg/kg/d) for 5 days. Apheresis was performed on 2 consecutive days.nnnRESULTSnThe median cell content of the two apheresis was 11.9 x 10(8) WBC/kg, 3.2 x 10(8) CD3/kg, and 8.3 x 10(6) CD34/kg. The median time to achieve an absolute neutrophil count (ANC) > or = 500/microL was 13 days, and 14 days to a platelet count > or = 50,000/microL. All patients engrafted. Platelet recovery was faster in marrow historic control groups. Blood cells in all tested cases contained more than 95% donor cells on day 30. The actuarial incidence of acute GVHD was 37%, and 13% for grade II-IV GVHD. Limited, corticosteroid responsive, chronic GVHD developed in 33% of assessable patients. At a median follow-up of 192 days, actuarial survival was 75%.nnnCONCLUSIONnTransplantation of a high number of stem cells may lead to rapid engraftment without the use of posttransplant colony-stimulating factors. GVHD does not appear to be more severe than in similarly treated patients undergoing bone marrow transplantation. For allogeneic transplantation, mobilized blood cell collections are an alternative to bone marrow collections.

Prevention of Legionella Infections in a Bone Marrow Transplant Unit: Multifaceted Approach to Decontamination of a Water System

OBJECTIVEnTo evaluate measures intended to reduce Legionella infections in patients undergoing bone marrow transplantation (BMT).nnnDESIGNnOngoing clinical and microbiological surveillance for Legionella colonization or infection was undertaken. All neutropenic patients with pulmonary infiltrates and fever unresponsive to broad-spectrum antibiotics were tested for Legionella organisms.nnnSETTINGnA 505-bed medical-surgical hospital with a designated BMT unit.nnnPATIENTSnTwo hundred twenty-five patients underwent BMT; 201 were treated on a new BMT unit. The incidence of Legionella infections was compared to that seen in an estimated 150 neutropenic patients treated on other units.nnnINTERVENTIONnA combined approach to decontamination of a hospital water supply was assessed. This included heating, particulate filtration, ultraviolet sterilization, and monthly pulse hyperchlorination of water supplied to the BMT unit. The incidence of Legionella infections was assessed on the BMT unit and compared with the frequency elsewhere in the hospital.nnnRESULTSnThere were only three cases of Legionella pneumonia among 201 patients undergoing transplantation on a new BMT unit. In contrast, 33 cases of Legionella infections were detected from approximately 150 patients treated on general medical floors.nnnCONCLUSIONnA multifaceted approach to decontamination of a hospital water system led to a marked reduction in Legionella infections.

Pentoxifylline and ciprofloxacin in patients with myelodysplastic syndrome. A phase II trial.

Tumor necrosis factor (TNF) inhibits hematopoietic cell proliferation. The combination of pentoxifylline (PTX) and ciprofloxacin (Cipro) has been previously shown to reduce circulating serum levels of TNF. In this Phase II trial 14 patients with advanced myelodysplastic syndrome were treated with PTX (2,000 mg/day) and Cipro (1,000 mg/day) in order to determine tolerability and effect on peripheral blood cell counts, progenitor cell responsiveness to cytokines and circulating serum levels of interleukin-6 (IL6) and TNF. Toxicity attributed to PTX and Cipro were limited to nausea in 4 patients. Peripheral blood cell counts, platelet transfusion requirements and red blood cell transfusion requirements did not change during administration of PTX and Cipro (daily for 28 days). Marrow progenitor cells of patients entered into trial were less responsive to stimulation with cytokines in vitro at baseline and during the trial compared to normal volunteers. Eight patients had elevated IL6 levels before treatment with PTX and Cipro these levels did not change during therapy. Five patients had elevated TNF levels at baseline. There was a suggestion of decreased TNF levels during treatment with PTX and Cipro (P = .09). In conclusion, PTX and Cipro was well tolerated but no evidence of efficacy was observed.

Disposition of total and unbound etoposide following high-dose therapy

Total and unbound etoposide pharmacokinetics were studied in 16 adult patients (median age, 34 years; range, 18–61 years) undergoing autologous bone marrow transplantation for advanced lymphoma after receiving high-dose etoposide (35–60 mg/kg) as a single intravenous infusion. Pretreatment values for mean serum albumin and total bilirubin were 3.0±0.4 g/dl and 0.5±0.4 mg/dl, respectively. Etoposide plasma concentrations and protein binding (% unbound) were determined by high-performance liquid chromatography (HPLC) and equilibrium dialysis, respectively. Pharmacokinetic parameters for unbound and total etoposide were calculated by nonlinear regression analysis using a two-compartment model. Te mean (±SD) parameters for total etoposide included: clearance (CL), 31.8±17.7 ml min−1 m−2; volume of distribution (Vss), 11.5±5.9 l/m2, and terminal half-life (t1/2 β), 7.2±3.7 h. Mean unbound CL was 209.6±62.7 ml min−1 m−2 and %unbound was 16%±5%. The mean etoposide %unbound was inversely related to serum albumin (r2=0.45,P=0.0043). The mean %unbound at the end of the etoposide infusion was higher than that at the lowest measured concentration (21% vs 13%, respectively;P=0.017), suggesting that concentration-dependent binding may occur after high etoposide doses. The median total CL was higher in patients with serum albumin concentrations of ≤3.0 g/dl than in those with levels of >3.0 g/dl (34.6 vs 23.5 ml min−1 m−2,P=0.05). Total CL was directly related to %unbound (r2=0.61,P=0.0004). Unbound CL was unrelated to either serum albumin or %unbound. These results demonstrate that hypoalbuminemia is independently associated with an increased etoposide %unbound and rapid total CL after the administration of high-dose etoposide. Unbound CL in hypoalbuminemic patients is unchanged in the presence of normal total bilirubin values.

Phase II study of roquinimex in myelodysplastic syndrome.

A Phase II clinical trial was undertaken using roquinimex (Linomide) in patients with myelodysplastic syndromes (MDS). Roquinimex is an orally active drug with immunostimulating activities demonstrated in vitro and clinically. Seventeen patients with MDS were enrolled in the study. Eligibility was limited to cytopenic patients with <20% marrow blasts. The drug was given orally twice weekly for 12 weeks with frequent monitoring of clinical, hematologic, and immunologic parameters. An increase in CD8+ and CD56+/CD3- cells was detected by 3 weeks. There was, however, no augmentation of natural killer or lymphokine-activated killer cell activity; progenitor cells were unchanged. Four patients had improvement in neutrophil counts, and two patients had improvement in platelet counts. Despite this improvement, the responses were transient or not maintained after discontinuation of therapy. One patient with RAEB, who was red cell transfusion dependent, experienced a complete remission that has persisted 14 months after completion of therapy. Adverse events developed in >25% of patients and included arthralgia, fever, headache, and myalgia. These side effects led to early withdrawal of therapy in five patients. These findings suggest that roquinimex may be of occasional benefit to patients with myelodysplastic syndromes.

Ex vivo purging of allogeneic marrow with L-Leucyl-L-leucine methyl ester. A phase I study.

L-Leucyl-L-leucine methyl ester (LLME) is a lysosomatropic compound that is converted by dipeptidyl peptidase I to metabolites that are membranolytic for cytotoxic T cells, NK cells, and LAK cells. Ex vivo treatment of murine marrow with LLME ameliorates acute graft-versus-host-disease (GVHD), which led to consideration of a clinical study. A phase I study design was initiated to evaluate the effects of ex vivo purging of allogeneic marrow on engraftment, since LLME also suppresses human progenitor cells. All patients received a preparative regimen of cyclophosphamide plus total body irradiation. GVHD prophylaxis consisted of cyclosporine +/- corticosteroids. This study included 19 patients with high risk disease undergoing allogeneic transplantation from an HLA-identical sibling (n = 12) or a partially HLA-matched family donor (n = 7). Marrow mononuclear cells were treated ex vivo in a dosage escalation study with LLME concentrations of 0.25 mM, 0.375 mM, and 0.5 mM. Marrow NK and LAK activities were essentially eliminated at concentrations > or = 0.375 mM LLME. CD8+ cells were also reduced. Granulocyte macrophage colony-forming unit recovery was 3% at 0.5 mM LLME. The median time to an absolute neutrophil count of 500/microliters was 17 days after transplantation (95% confidence interval = 14-18 days). One patient that received marrow treated with 0.5 mM LLME died of secondary graft failure. Complete donor chimerism was documented in each evaluable case. NK recovery was delayed at LLME concentrations > or = 0.375 mM LLME. Grade II/IV GVHD occurred in 4/18 evaluable patients. Ex vivo treatment of human marrow with LLME diminishes NK activity, LAK activity, CD8+ cells, and granulocyte macrophage colony-forming units, but does not totally prevent acute GVHD.

Reduction of Allogeneic Transplant Morbidity by Combining Peripheral Blood and Bone Marrow Progenitor Cells

One case has been reported of a patient undergoing allogeneic transplantation with peripheral blood progenitor cells (PBPCs) rather than bone marrow. We now report the first case of a patient who underwent an allogeneic transplant with bone marrow combined with PBPCs.