The efficacy of prophylactic outpatient antibiotics for the prevention of neutropenic fever associated with high-dose etoposide (VP-16) for stem cell mobilization.

High-dose etoposide (2 g/m(2)) plus G-CSF is a very effective regimen for peripheral blood progenitor cell (PBPC) mobilization. Unfortunately, neutropenia is common. The infectious complications associated with high-dose etoposide have not been previously described. After noting a high incidence of hospitalizations for neutropenic fever, we began a vigorous prophylactic antibiotic regimen for patients receiving high-dose etoposide plus G-CSF, attempting to reduce infectious complications. Ninety-eight patients underwent etoposide mobilization between December 1997 and June 2000. Three chronological patient groups received: (1) no specific antibiotic prophylaxis (n = 44); (2) vancomycin i.v., cefepime i.v., clarithromycin p.o., and ciprofloxacin p.o. (n = 27); and (3) vancomycin i.v., clarithromycin p.o., and ciprofloxacin p.o. (n = 27). The patients not receiving antibiotic prophylaxis had a 68% incidence of hospitalization for neutropenic fever. In the patients receiving prophylaxis, the incidence was reduced to 26% and 15% respectively, for an overall incidence of 20% (P < 0.001 for comparison between prophylaxed and unprophylaxed groups). We conclude that etoposide mobilization is associated with a significant incidence of neutropenic fever, which can be substantially reduced by a vigorous antimicrobial prophylactic program.

Infectious complications within the first year after nonmyeloablative allogeneic peripheral blood stem cell transplantation.

Nonmyeloablative peripheral blood stem cell transplantation (PBSCT) is a novel therapeutic strategy for patients with malignant and non-malignant hematologic diseases. Infectious complications of this procedure have not been previously well described. Data on 12 patients transplanted at a tertiary care center were collected prospectively and verified retrospectively. Neutropenia developed in a third of patients, lasting for a median of 5 days. All patients developed some degree of graft-versus-host disease, as intended. Most patients achieved full chimerism by week 5. Bacterial infections occurred in two patients (17%). Cytomegalovirus (CMV) viremia occurred in five patients (42%) at a median of 80 days; none had received CMV prophylaxis. Viremia was associated with fever and fatigue in three patients, possible gastrointestinal involvement in one patient and was asymptomatic in one patient. All viremic patients responded to intravenous ganciclovir therapy. No fungal infections were documented. No patients died as a result of infection. The incidence of CMV viremia in our patients was high, but the incidence of invasive disease due to CMV was low. The best strategy to prevent CMV in patients undergoing nonmyeloablative PBSCT remains to be determined, but strategies employed in traditional allogeneic bone marrow transplantation should be considered in these patients.

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.

Progressive disease after ABMT for Hodgkin's disease.

A major limitation of ABMT for relapsed/refractory Hodgkin's disease is disease recurrence post-transplantation. We retrospectively reviewed 68 patients undergoing ABMT from January 1987 to June 1993. All received a uniform preparatory regimen (CBV). The median patient age was 30; 75% received prior radiation therapy and all patients received prior chemotherapy. Thirty-one percent presented at the time of transplantation with tumor masses larger than 10 cm. Sixty-two percent received autologous marrow alone and 38% PBPC with or without autologous bone marrow. Overall and progression-free survival are 43 and 36% at 5 years. Median follow-up for survivors is 59 months. Multivariate analysis revealed that tumor bulk was the most powerful poor prognostic factor for both survival and progression-free survival. Those transplanted with non-bulky tumors had an overall survival and progression-free survival of 52 and 44%, respectively, compared to those transplanted with bulky tumors who had an overall survival and progression-free survival of 22 and 16% (P = 0.03 and P = 0.04, respectively). Twenty-seven patients have relapsed. Four relapsed more than 2 years after ABMT. Four of the 27 patients who have relapsed remain alive, two without evidence of disease. The time after transplant to relapse was prognostically important, with no patients who relapsed within 6 months of ABMT still being alive, compared with 25% of patients who relapsed 7 or more months after ABMT who are still alive. We conclude that salvage therapy for relapse after ABMT is appropriate, as some patients may achieve prolonged survival. The time from transplant to relapse is an important survival predictor.

High-dose busulfan and cyclophosphamide followed by autologous bone marrow transplantation and/or peripheral blood progenitor cell rescue for metastatic breast cancer.

High doses of combination alkylating agents have shown promise in the treatment of breast cancer but are complicated by significant toxicity. Busulfan and cyclophosphamide (BuCy) is a high-dose combination alkylating agent regimen that is well-tolerated when given for hematologic malignancy. We prospectively studied the effects of BuCy followed by autologous bone marrow transplant (ABMT) or peripheral blood progenitor cell (PBPC) rescue in 21 patients with metastatic breast cancer who had responded to either standard chemotherapy or radiotherapy. The mean patient age was 44 years. Nine patients were either estrogen- or progesterone-receptor positive, ten were negative, and two were unknown. Fourteen patients had local recurrence, ten had bone metastases, six had visceral disease, and two had a nonlocal soft tissue recurrence. Busulfan 16 mg/kg and cyclophosphamide 120 mg/kg (BuCy2) was given and followed by either ABMT, PBPC rescue, or both. Grade III to IV extramyeloid toxicity occurred in 6 (29%) patients. One patient died of hepatic venoocclusive disease but there was no other treatment-related mortality. Pulmonary infiltrates with hypoxia of uncertain origin developed in 2 patients after discharge. Of the 10 patients with measurable disease, 4 had complete responses, and 3 had partial responses to high-dose therapy for a total response rate of 70%. The estimated 2-year disease-free survival is 25% (95% CI = 6% to 44%). Our study found BuCy to be a well-tolerated preparative regimen for ABMT in the treatment of patients with metastatic breast cancer.

G-CSF primed peripheral blood progenitor cells in autologous bone marrow transplantation: parameters affecting bone marrow engraftment.

G-CSF and GM-CSF enhance the rate of neutrophil engraftment in autologous bone marrow transplantation (ABMT) without significantly affecting platelet engraftment. Peripheral blood progenitor cells (PBPC) may enhance rates of engraftment of both neutrophils and platelets. We treated 49 patients undergoing ABMT with a course of G-CSF to obtain PBPC and infused these cells post-transplant with G-CSF in an attempt to determine factors which might correlate with enhanced BM engraftment. Forty-nine patients with Hodgkin's disease, non-Hodgkin's lymphoma or breast cancer undergoing unpurged ABMT were studied. G-CSF priming consisted of an outpatient 8 day course of 5 micrograms/kg/day followed by three leukaphereses (on day 5, 7 and 8) to collect PBPC. Patients then received a chemotherapeutic BMT preparative regimen followed by an infusion of PBPC, autologous BM and the reinstitution of G-CSF (16 micrograms/kg/day). BM engraftment was rapid. The median time to achieve 0.5 x 10(9)/l neutrophils was 10 days compared with a historical BMT control patient population receiving the same preparative regimens of 19 days (p = 0.001). Time to achieve a platelet count of 20 x 10(9)/l was 16 days compared with a historical control of 22 days (p = 0.001). Neutrophil engraftment occurred in all patients by day +14. Marrow engraftment correlated with the total number of CD34+ cells infused as well as the total number of mononuclear cells infused but not the total number of CD34+/CD33- cells infused. The amount of total blood volume pheresed significantly correlated with yield of total mononuclear cells. Prior exposure to radiation therapy negatively correlated with progenitor cell yield.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis of mannosylglucosaminylinositol phospholipids in normal but not paroxysmal nocturnal hemoglobinuria cells.

To identify mannosyl (Man)-containing intermediates of the human glycoinositol phospholipid (GPI) anchor pathway and examine their expression in paroxysmal nocturnal hemoglobinuria (PNH), mannolipid products deriving from in vitro guanosine diphosphate [3H]Man labeling of HeLa cell microsomes were characterized. The defined GPI species were correlated with products deriving from in vivo [3H]Man labeling of normal and (GPI-anchor defective) affected leukocytes. In vitro analyses in HeLa cells showed dolichol-phosphoryl (Dol-P)-[3H]Man and a spectrum of [3H]Man lipids exhibiting TLC mobilities approximating those of Trypanosoma brucei (Tryp) GPI precursors. Iatrobead HPLC separations and partial characterizations of the major isolated [3H]Man species (designated H1-H8) showed that all but H1 (Dol-P-Man) were sensitive to HNO2 deamination and serum GPI-specific phospholipase D digestion but were resistant to phosphatidylinositol-specific phospholipase C digestion unless previously deacylated with mild alkali. [3H]Man label in H3, H4, and H6 but not in H5 or H7 was efficiently released into the aqueous phase by jack bean alpha-mannosidase digestion. BioGel P-4 and AX-5 sizing of the dephosphorylated core glycan fragments of H6 and H7 gave values that coincided precisely with the corresponding glycan fragments from the fully assembled Tryp anchor donor A' (P2). Affected leukocytes from four patients with PNH supported formation of GlcNAc- and GlcN-PI but all failed to express H6 and H7 as well as H8 and two showed complete absence of earlier Man-containing intermediates. These findings argue that human intracellular GPI mannolipids are built on acylated inositol phospholipids, that H6 and H7 contain differentially phosphoethanolamine-substituted Man3-GlcN-inositol cores, and that PNH cells are defective in conversion of GlcN-PI into these more mature mannolipid structures.