Economic analysis of conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer.

We performed an economic analysis of data from 180 women in a clinical trial of conventional-dose chemotherapy vs high-dose chemotherapy plus stem-cell transplantation for metastatic breast cancer responding to first-line chemotherapy. Data on resource use, including hospitalizations, medical procedures, medications, and diagnostic tests, were abstracted from subjects' clinical trial records. Resources were valued using the Medicare Fee Schedule for inpatient costs at one academic medical center and average wholesale prices for medications. Monthly costs were calculated and stratified by treatment group and clinical phase. Mean follow-up was 690 days in the transplantation group and 758 days in the conventional-dose chemotherapy group. Subjects in the transplantation group were hospitalized for more days (28.6 vs 17.8, P=0.0041) and incurred higher costs (US dollars 84055 vs US dollars 28169) than subjects receiving conventional-dose chemotherapy, with a mean difference of US dollars 55886 (95% CI, US dollars 47298-US dollars 63666). Sensitivity analyses resulted in cost differences between the treatment groups from US dollars 36528 to US dollars 75531. High-dose chemotherapy plus stem-cell transplantation resulted in substantial additional morbidity and costs at no improvement in survival. Neither the survival results nor the economic findings support the use of this procedure outside of the clinical trial setting.

High-dose cyclophosphamide for severe systemic lupus erythematosus.

Cytotoxic therapy is a cornerstone for patients with severe systemic lupus erythematosus (SLE). High-dose cyclophosphamide, 200 mg/kg, can induce a complete remission without the need for stem cell rescue in patients with autoimmune illnesses. Here we report on our first four patients treated for severe SLE with this treatment approach. Patients received cyclophosphamide, 200 mg/kg, divided over 4 days. Starting day 10, patients received filgrastim, 5 micrograms/kg/day, until their absolute neutrophil count (ANC) rose to 10.0 x 10(9)/l for two consecutive days. Disease activity as evaluated by scores from the Systemic Lupus Activity Measure-2, the SLE Disease Activity Index and the Responder Index for Lupus Erythematosus were completed before and after high-dose therapy. Before high-dose cyclophosphamide, SLE disease duration ranged from 8 to 21 (mean 12.5) years. Their average disease activity measured by SLAM-2 and SLEDAI was 15.5 (range 11-19) and 23.25 (range 20-26), respectively. At a median of 22 (range 12-39) months of follow-up, mean disease activity measured by SLAM-2 and SLEDAI decreased to 6.25 and 7.75, respectively. All patients experienced febrile neutropenia. No long-term morbidities or mortalities were observed. High dose cyclophosphamide is a therapy capable of decreasing disease severity in poor prognosis SLE patients. Future study is warranted for both refractory patients as well as primary therapy for patients with moderate to severe disease presentations.

High-dose cyclophosphamide without stem-cell rescue for refractory CIDP.

Four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who were refractory to conventional treatment were treated with high-dose cyclophosphamide (200 mg/kg over 4 days). All improved in functional status and muscle strength. Nerve conduction studies improved in three of four. Other immunomodulatory medications have been discontinued. High-dose cyclophosphamide can be given safely to patients with CIDP and patients with disease persistence after standard therapy may have a response that lasts for over 3 years and results in long-term disease remission.

Use of granulocyte colony-stimulating factor after high-dose chemotherapy and autologous peripheral blood stem cell transplantation: what is the optimal timing?

Administration of granulocyte colony-stimulating factor to patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation accelerates neutrophil recovery and decreases hospitalization time. The optimal timing for granulocyte colony-stimulating factor infusion remains unknown. In this retrospective, case-controlled, two-armed study, we reviewed our experience at Hahnemann University Hospital to determine whether initiating granulocyte colony-stimulating factor infusions on posttransplant day 0 versus day 8 affects neutrophil recovery time, posttransplant discharge date, total hospital days after high-dose chemotherapy, and autologous peripheral blood stem cell transplantation. All patients hospitalized between 1994 and 1998 at Hahnemann University Hospital, Bone Marrow Transplantation Unit with breast cancer or non-Hodgkin's lymphoma, who underwent high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation and received granulocyte colony-stimulating factor either on posttransplant day 0 (16 patients) or day 8 (16 patients). The day 0 and day 8 groups had no statistically significant differences in age, sex, weight, height, body surface area, disease characteristics, pretransplant harvesting or conditioning regimens, or transplant CD34+ cell counts. Our main outcome measure was the mean time to reach absolute neutrophil count greater than or equal to 0.5 x 10(9)/l, the number of hospital days after transplant, and the total hospital days. The mean days to neutrophil recovery (10.56 versus 9.68, p = 0.48), posttransplant hospital days (13.62 versus 12.81, p = 0.39), and total hospital days (20.25 versus 20.25, p = 1.00) were not significantly different between day 8 and day 0 groups, respectively. No significant effects on neutrophil recovery time, posttransplant hospital days, or total hospital days were observed with the initial granulocyte colony-stimulating factor infusion on day 0 versus day 8 after transplant. Delayed administration may allow substantial cost savings (US$200 x 8 approximately equal to US $1,600 per patient) without affecting clinical outcome. More studies are needed to determine whether greater delay is feasible.

Hepatic dysfunction following busulfan and cyclophosphamide myeloablation: a retrospective, multicenter analysis.

Veno-occlusive disease continues to be a significant cause of morbidity and early mortality following bone marrow transplantation. This study retrospectively analyzes the incidence and risk factors for severe VOD in 350 patients treated with 4 days of busulfan (total 16 mg/kg) and 2 days of cyclophosphamide (120 mg/kg) at four marrow transplant centers. Using the criteria defined by McDonald et al (Hepatology 1984; 4: 116-122), 93/350 (27%) developed VOD (11% mild, 5% moderate and 11% severe). Multivariate analysis revealed the following risk factors to be significantly associated with severe VOD: pretransplant transaminase and alkaline phosphatase elevation, ciprofloxacin antibiotic prophylaxis, use of estrogen/progestins or vancomycin during the peritransplant period and methotrexate for GVHD prophylaxis. Mild to moderate grades of VOD were not associated with significantly increased mortality but mortality was higher in patients with severe VOD (31%, P = 0.0013). These data suggest that risk factors for VOD may depend on the preparative regimen used and suggest that use of these risk factors may identify a subgroup of patients that can be targetted for studies of prevention of VOD.

Unrelated donor bone marrow transplantation without T cell depletion using a chemotherapy only condition regimen. Low incidence of failed engraftment and severe acute GVHD.

Twenty-five patients with hematologic malignancies were treated with busulfan (16 mg/kg) and cyclophosphamide (50 mg/kg x 3 days) as conditioning for bone marrow transplantation using marrow from serologically matched, DR locus genotypically identical unrelated donors. Previous studies of BuCy2 as conditioning for UD-BMT have reported a graft failure rate of up to 21% suggesting it may be insufficiently immunosuppressive in this setting. We elected not to use BuCy4 as it may have a higher incidence of extramedullary toxicity. In addition the patients received GM-CSF (500 mg/m2) from day 0, cyclosporine and short-course methotrexate (15 mg/m2 x 1, then 10 mg/m2 x 3) as GVHD prophylaxis and prophylactic ganciclovir at engraftment if either they or their donor were CMV antibody positive. The median age of the 25 patients was 41 years and the most common diagnosis was CML (76%). Seven patients were considered poor risk and eight males were recipients of marrow from female donors. Sixteen patients survive at a median of 435 days from transplant. The actuarial overall and disease-free survivals at 1 year in this group of older patients were 62 +/- 20% and 57 +/- 20% and 100-day survival was 70%. The engraftment rate was 100%; there have been no instances of secondary graft failure. Fifteen patients (60%) developed grade II-IV GVHD and 12 of 16 (75%) developed some chronic GVHD but only half of these were extensive. The performance status of survivors is good (median of 90); seven of 12 eligible patients are back at work. This study demonstrates that UD-BMT can be successfully performed in very closely HLA-matched older patients using a chemotherapy-only protocol and that low rates of severe acute GVHD can be achieved without T cell depletion.

Extramedullary toxicity of a conditioning regimen containing busulphan, cyclophosphamide and etoposide in 84 patients undergoing autologous and allogenic bone marrow transplantation.

Relapse is still a common problem after bone marrow transplant (BMT) and teh value of adding etoposide to standard conditioning agents is being tested. The aim of the study was to assess the extramedullary toxicity which resulted from adding etoposide to busulphan 16 mg/kg and cyclophoshamide 120 mg/kg (BuCY2). Eighty four patients received etoposide 40 mg/kg in addition to BuCY2 as conditioning for autologous and allogeneic BMT for leukemia and lymphoma. The Bearman system of grading extramedullary toxicity was used along with a system of grading skin toxicity that we devised. There were seven acute toxic deaths (8%) and in total 15 patients experienced life-threatening or fatal toxicity. The major finding was a striking increase in pulmonary toxicity with six deaths (five alveolar hemorrhage and one pulmonary embolus). Five of seven of the patients with severe pulmonary toxicity had been given irradiation to the lung fields (P < 0.001). Thirty nine per cent of patients had veno-occlusive disease of the liver but the case fatality rate was low (1 of 33). Dermatologic toxicity was experienced by 82% of patients and was symptomatically troublesome but rapidly reversible. The addition of etoposide to BuCY2 increases non-hematological toxicity. This regimen is associated with severe pulmonary toxicity in patients with a history of prior chest irradiation. A high incidence of skin toxicity was seen; a system for describing this toxicity is proposed.

Transient high grade heart block following autologous bone marrow infusion.

We performed a retrospective analysis of 42 consecutive patients undergoing autologous BMT to determine the incidence of second and third degree heart block following the infusion of cryopreserved autologous bone marrow and to identify any predisposing characteristics. A decrease in heart rate > or = 10 beats/min was observed in 80.5% of patients, with a mean decrement of 27 +/- 7 beats/min. 48.8% of patients developed absolute bradycardia (< or = 60 beats/min). Four of 41 patients (9.7%) experienced high-grade heart block: 9.7% second degree and 4.8% third degree. Heart block patients did not differ from the non-heart block group with respect to age, interval from diagnosis or bone marrow harvest to transplant, cardiac risk factors, pretransplant electrocardiograms or radionuclide angiograms, transplant chemotherapy regimens or serum chemistry values. There was an increased incidence of heart block in patients with prior exposure to cyclophosphamide (p < 0.05) and vinca alkaloids (p < 0.05). There appears to be a high incidence of transient second and third degree heart block following autologous marrow infusion. This may be related to prior chemotherapy, but more likely is an effect of the infusate itself. Predisposing factors were not identified.