Therapy-related myelodysplasia and leukemia occur infrequently following VP-16 priming and autotransplantation without total body irradiation.

The use of VP-16 for stem cell mobilization has been cited as a significant risk factor for the development of therapy-related myelodysplasia/leukemia (tMDS/tAML) following autologous transplantation. The present study analyzed a large cohort of patients who underwent autotransplantation following stem cell mobilization with VP-16 and radiation-free preparation in order to determine the risk of tMDS/tAML. The estimated incidence of 9.9% at 7 years suggests that in the absence of TBI, VP-16 priming is not associated with an increased incidence of tMDS/tAML.

Busulfan levels are influenced by prior treatment and are associated with hepatic veno-occlusive disease and early mortality but not with delayed complications following marrow transplantation.

Long-term outcome was analyzed in 28 patients transplanted between 1989 and 1992 following busulfan and cyclophosphamide and who had busulfan levels studied. While there was no significant correlation of busulfan levels with diagnosis, patients who had received extensive prior chemotherapy had a significantly higher area under the curve (AUC; P = 0.02) and maximum busulfan levels (Cmax; P = 0.03). High AUC was associated with the development of hepatic veno-occlusive disease (P = 0.03) and with early transplant-related mortality (P = 0.06). No significant correlation of busulfan levels with relapse, late non-relapse death, late complications, nor event-free survival was detected.

The influence of early transplantation, age, GVHD prevention regimen, and other factors on outcome of allogeneic transplantation for CML following BuCy.

Results in 164 patients who underwent allogeneic marrow transplantation following busulfan and cyclophosphamide over a 15 year period were analyzed. Age (median 37, range 14-66 years) did not significantly affect the incidence of graft-versus-host disease (GVHD), but patients who received methotrexate with cyclosporine had a significantly lower incidence (P = 0.002) of chronic GVHD compared to those who received methylprednisolone with cyclosporine. Hepatic veno-occlusive disease (VOD) occurred less frequently in chronic phase patients (P = 0.002) and in those transplanted shortly after diagnosis (P = 0.001). Five year leukemia-free survival (LFS) for the entire group was 49% (95% CI 41-57%). For 102 patients who underwent transplantation in chronic phase, results were significantly improved by transplantation at a short interval following diagnosis, particularly within 3 months (P = 0.01), by the use of methotrexate and not corticosteroids for GVHD prevention (P = 0.03), and by use of HLA-identical sibling donors (P = 0.01). Age was not a significant adverse prognostic factor and transplantation was successfully performed in individuals up to age 66. Allogeneic transplantation in CML, including older patients and those with unrelated donors, can be most safely and effectively performed shortly after diagnosis.

Analysis of prognostic factors for allogeneic marrow transplantation following busulfan and cyclophosphamide in myelodysplastic syndrome and after leukemic transformation.

Prognostic factors in 42 patients aged 11 to 62 (median 46) years, with myelodysplastic syndrome (MDS) or after leukemic transformation, who underwent allogeneic marrow transplantation between 1984 and 1999 were analyzed. Thirty-six had advanced disease morphology; 19 had leukemic transformation. Twenty-nine received a preparative regimen of BuCy2 and 13 busulfan 14 mg/kg, etoposide 50 mg/kg and cyclophosphamide 120 mg/kg. Severe hepatic veno-occlusive disease (VOD) occurred in three patients all of whom received anti-leukemic chemotherapy prior to transplantation. Fifteen patients (36%) died from early transplant-related complications; nine patients relapsed. The estimated 4 year disease-free survival (DFS) was 35% (95% CI 26-44%). Older age was the most significant adverse prognostic factor. Patients with leukemic transformation who underwent early transplantation had significantly better DFS than those treated first with chemotherapy (P = 0.002). Delayed toxicity was rare in these patients; no late relapses occurred. Bone Marrow Transplantation (2000) 25, 1219-1222.

Autotransplantation following busulfan, etoposide and cyclophosphamide in patients with non-Hodgkin's lymphoma.

The purpose of the study was to determine the toxicities and effectiveness of a novel preparative regimen of busulfan (Bu) 14 mg/kg, etoposide 50 or 60 mg/kg, and cyclophosphamide (Cy) 120 mg/kg in non-Hodgkin's lymphoma (NHL) and to analyze results using doses based on different body weight parameters and the two different etoposide doses. Three hundred and eighty-two patients aged 16 to 72 underwent first autologous transplantation with mobilized peripheral blood progenitor cells between August 1992 and December 1998 at either of two transplant centers. Mucositis was the most common toxicity. Hepatic toxicity was the most common life-threatening toxicity; severe hepatic VOD occurred in 11 patients (2.9%). Ten patients (2.6%) died from treatment-related toxicity. The 3-year progression-free survival (PFS) for the entire group was 46.9% (95% CI, 40.5-53.3%). Elevated LDH, resistance to chemotherapy, and intermediate/aggressive histology were significant adverse prognostic factors. For patients in sensitive first relapse PFS was 47.0% (95% CI, 37-57%). Neither etoposide dose nor body weight parameter utilized significantly affected outcome. In conclusion, the novel preparative regimen of Bu, etoposide and Cy results in a low incidence of treatment-related mortality and is effective in the treatment of patients with NHL. Bone Marrow Transplantation (2000) 25, 1243-1248.

Mobilization of peripheral-blood progenitor cells with high-dose etoposide and granulocyte colony-stimulating factor in patients with breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease.

PURPOSE: We analyzed the safety and effectiveness of high-dose etoposide (2 g/m2) followed by granulocyte colony-stimulating factor (G-CSF) as a peripheral-blood progenitor cell (PBPC) mobilization regimen and assessed extent of tumor reduction in patients with breast cancer, non-Hodgkin's lymphoma (NHL), and Hodgkin's disease (HD). PATIENTS AND METHODS: One hundred sixty-nine consecutive patients who eventually underwent PBPC transplantation received treatment with high-dose etoposide (2 g/m2) followed by daily G-CSF (5 microg/kg). RESULTS: This mobilization method was effective in nearly all patients. No patients died of mobilization-related complications. A 50% reduction in tumor size was seen in 19% of assessable patients with breast cancer, 44% of those with NHL, and 38% of those with HD. Hematopoietic recovery (HR) following transplantation occurred in all patients. Patients with > or = 4 x 10(6) CD34+ cells/kg engrafted with neutrophils at a median of 9 days after transplant and patients with at least 1.2 x 10(6) CD34+/CD33- cells/kg achieved platelet recovery at a median of 15 days. CONCLUSION: Etoposide plus G-CSF is an effective and safe method for mobilization of PBPCs. Etoposide is an effective agent in tumor reduction in NHL and HD and is less effective in breast cancer. The substantially lower incidence of prior exposure to this agent compared with cyclophosphamide favors its use.

Cytomegalovirus prophylaxis and treatment following bone marrow transplantation.

OBJECTIVE: To provide an overview of the role of cytomegalovirus (CMV) in the bone marrow transplant (BMT) population and update the current methods of prevention and treatment of CMV infection and disease, with emphasis on CMV interstitial pneumonia (CMV-IP). DATA SOURCES: The current medical literature, including abstracts presented at recent national and international meetings, is reviewed. References were identified by searching the MEDLINE database from January 1988 through June 1994. The reference lists of the published studies and reviews obtained from the initial literature search were reviewed as well. STUDY SELECTION: Data regarding the epidemiology of CMV, the risk factor associated with CMV infection and disease, as well as data on the prevention and the treatment of CMV infection and disease in the BMT population are cited. Specific attention was focused on randomized, placebo-controlled studies pertaining to the prevention of CMV infection and disease in CMV-immunoglobulin G positive recipients undergoing allogeneic BMT. Information from nonrandomized, placebo-controlled studies was included in the absence of stronger data. DATA EXTRACTION: Information contributing to CMV in the BMT population was reviewed. Data supporting and disputing specific preventive and treatment modalities are presented. DATA SYNTHESIS: The incidence of CMV seropositivity in the general population is high and while BMT becomes a widely accepted treatment modality, CMV reactivation and subsequent disease, especially CMV-IP, becomes a significant prognostic factor of morbidity and mortality. Even though antiviral agents such as ganciclovir and foscarnet can inhibit the viral replication in vivo, they have not been able to treat CMV-IP effectively. It has been suggested that CMV-IP is an immunopathologic process that can cause irreversible damage, hence, the low efficacy of antiviral therapy and the associated high mortality. Immunomodulating agents such as intravenous immune globulin and cytomegalovirus hyperimmune globulin can increase the efficacy of antivirals in the treatment of CMV-IP. This further supports the postulated immunopathologic process of this disease. The lack of understanding of the pathophysiology of the disease compromised the efforts of treatment and led to the development of preventive interventions with antiviral and immunomodulatory regimens that resulted in a significantly lower incidence of infection and disease. As a result of current data, the Eastern Cooperative Oncology Group has published guidelines for the prevention and treatment of CMV infection and disease. CONCLUSIONS: The prognosis of CMV disease in the BMT recipients has improved as a result of a wide variety of modifications in the management of BMT recipients. These include an increased understanding of the risk factors associated with CMV infection, routine screening for CMV replication and excretion, and more effective prophylactic regimens. Still, more than half of the patients who develop pneumonia will die, indicating that more studies are needed to increase the understanding of the pathophysiology and refine the preventive and therapeutic regimens against CMV.

Influence of graft-versus-host disease on outcome following allogeneic transplantation with radiation-free preparative therapy in patients with advanced leukemia.

Between March 1984 and March 1995, 76 patients with advanced acute myelogenous, acute lymphoblastic, or chronic myelogenous leukemia underwent allogeneic marrow transplantation from HLA-identical or one-antigen mismatched sibling or unrelated donors. Patients received a preparative regimen consisting of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg or busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and etoposide (VP-16) 50 mg/kg. For GVHD prevention, patients received cyclosporine with either methotrexate or steroids or FK506 with methotrexate. Fourteen patients were leukemia-free survivors at a median of 6.5 years (range 1-11 years) following transplantation. For the group as a whole, the estimated leukemia-free survival (LFS) at 5 years is 20% (95% confidence interval 10-30%). Ten of the 14 leukemia-free survivors developed acute GVHD greater than grade II and chronic GVHD and two developed only chronic GVHD. Significantly better relapse rates and disease-free survival were associated with the development of acute and/or chronic GVHD. In the absence of acute GVHD and/or chronic GVHD, patients who underwent transplantation for advanced leukemia, after preparation with Bu/CY or Bu/CY/VP-16, were very likely to experience disease recurrence. Novel strategies designed to promote development of GVHD present a promising area for investigation to improve outcome in patients with leukemia at high risk for relapse.

Controlled trial of orally administered immunoglobulin following bone marrow transplantation.

Between May 1987 and September 1989, 72 patients undergoing marrow transplantation at a single institution were randomized to receive 50 mg/kg of a commercial gammaglobulin preparation or placebo daily in four divided doses for 28 days following transplantation. Patients receiving oral gammaglobulin had significantly increased concentrations of stool IgG (p = 0.01) compared with the placebo group. There was no difference in the amount of diarrhea, frequency of GVHD, duration of hospitalization or survival in the two groups. The present study demonstrates that orally administered IgG can survive passage through the gastrointestinal tract of bone marrow transplantation recipients but there was no effect of oral administration of immunoglobulin on morbidity or mortality following bone marrow transplantation.

Effect of multidose therapy on cerebrospinal fluid penetration of cefazolin.

The relationship between serum concentrations and cerebrospinal fluid (CSF) concentrations of cefazolin, and the association between these concentrations and neurotoxic reactions, were investigated. Samples of serum and spinal fluid were drawn simultaneously from six patients at the steady state on various dosages of cefazolin sodium for different conditions. The dose, dosing interval, number of doses, results of renal function tests, and signs of neurotoxicity, such as muscle twitches, confusion, and seizures, were recorded. The concentrations of cefazolin in the serum and CSF, total serum protein, and percent albumin were determined. Five of the six patients given multiple doses of cefazolin sodium had notable CSF accumulation of the drug (11.3 +/- 2.7% of the serum concentration). Three patients experienced generalized focal-motor seizures during their therapy. Neurotoxicity was found to be associated with renal dysfunction and multiple-dose therapy leading to serum concentrations greater than 360 micrograms/ml and CFS concentrations greater than 34 micrograms/ml. Cefazolin will penetrate into the CSF in patients receiving multiple-dose therapy of the drug. To avoid neurotoxicity, careful attention should be paid to the recommended dosage regimens, the impact of renal dysfunction on drug clearance should be recognized, and serum assays should be performed when necessary.

Seizures associated with high cerebrospinal fluid concentrations of cefazolin.

Three cases of generalized seizures in patients with high cerebrospinal fluid (CSF) concentrations of cefazolin are reported. Patient 1, a 60-year-old woman with impaired renal function and a Klebsiella pneumoniae infection, was treated with 70 mg every eight hours of i.v. gentamicin sulfate and 1.5 g every four hours of i.v. cefazolin sodium. Gentamicin was discontinued on day 11. On day 12, the patient had a generalized tonic-clonic seizure. Serum and CSF concentrations of cefazolin one day later were 470 and 64 micrograms/ml, respectively. Patient 2, a 70-year-old man with impaired renal function, was given i.v. cefazolin, 1 g every 12 hours; the dosage interval was shortened later to every six hours. Two days later, the patient had two tonic-clonic seizures. Serum and CSF concentrations eight hours after the last dose of cefazolin were 360 and 34 micrograms/ml, respectively. Patient 3, a 67-year-old woman with renal vein thrombosis, received 55 mg every eight hours of i.v. gentamicin and 2 g every six hours of i.v. cefazolin. The antibiotics were discontinued after eight days when the patient had two tonic-clonic seizures. Serum and CSF concentrations of cefazolin measured 28 hours later were 1000 and 106 micrograms/ml, respectively. Previous reports of cefazolin-associated seizures are reviewed. In patients with renal failure, cefazolin may obtain high CSF concentrations. To avoid seizures, cefazolin doses should be adjusted in these patients.