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We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m(2), day -4 to day -2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control.

Purpose: We described previously a prognostic model for high-risk primary breast cancer patients receiving high-dose chemotherapy (HDC). Such model included nodal ratio (no. involved nodes:no. dissected nodes), tumor size, hormone receptors, and HER2. In the present study we intended to test this model prospectively in a second patient cohort. In addition, we analyzed the long-term overall outcome of our HDC trials., Experimental Design: We analyzed all 264 patients enrolled since 1990 in our prospective trials for 4-9+, > or = 10+ nodes, or inflammatory disease. Patients of the second cohort (treated since 1997) had their prognostic score estimated prospectively before receiving HDC., Results: Fourteen patients (5.3%) died from HDC-related complications. At median follow-up of 7.1 years, relapse-free survival and overall survival of the whole group were 69.8% and 73%, respectively. Median time to relapse was 14 months (63.5% relapses within the first 2 years, 6.7% after year 5). The model was validated in the second cohort, establishing the following pretransplant risk categories: low risk (low score, HER2-), 44% patients, 87% freedom from relapse (FFR); intermediate risk (low score, HER2+), 29% patients, 68% FFR; and high risk (high score, any HER2), 27% patients, 49% FFR., Conclusions: Few relapses are seen after year 5 of follow-up, which indicates the need for mature results of the randomized trials before their final interpretation or meta-analysis. Our prospectively validated prognostic model, if additionally confirmed in the randomized trial populations, may provide an insight into the relative benefit of HDC in different risk patient subsets.

Background: Therapy with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) plus autologous bone marrow transplantation has been extensively studied as treatment for patients with stage II or III breast cancer who have a 70% or greater risk of developing metastatic disease. This therapy is being used in a cooperative intergroup phase III clinical trial. In the cyclophosphamide-cisplatin-BCNU regimen, cyclophosphamide and BCNU, but not cisplatin, have been reported to cause acute lung injury, suggesting that either cyclophosphamide or BCNU may contribute to this injury.Purpose: The purpose of this study was to analyze clinical and pharmacokinetic data from our ongoing phase II trials and to determine whether there is an association between BCNU pharmacokinetics and acute lung injury following cyclophosphamide-cisplatin-BCNU therapy.Methods: We performed a retrospective study of 38 patients treated following induction therapy or relapse, 29 with stage II-IV breast cancer and nine with intermediate and high-grade stage III-IV non-Hodgkin's lymphoma. These patients received therapy with cyclophosphamide at a dose of 1875 mg/m2 daily as a 1-hour intravenous infusion for 3 days, cisplatin at 55 mg/m2 per day as a 72-hour continuous intravenous infusion, and BCNU at 600 mg/m2 as a 2-hour infusion immediately following completion of the cisplatin infusion. Data from analysis of blood samples were used to calculate pharmacokinetic parameters for BCNU, and acute lung injury was determined on the basis of pulmonary function test results and histologic examination of lung biopsy specimens.Results: Our analysis showed that 20 (53%) of the 38 patients developed pulmonary injury following treatment. Twelve (60%) of the 20 had values for area under the curve (AUC) for BCNU concentration x time that exceeded 600 (micrograms/mL) x minute, whereas only two (11%) of the 18 without pulmonary injury had values above this level (P < .03). Thus, 12 (86%) of 14 patients with BCNU AUC greater than 600 (micrograms/mL) x minute developed lung injury.Conclusions: These results suggest that BCNU exposure greater than 600 (micrograms/mL) x minute is associated with increased risk of acute lung injury after cyclophosphamide-cisplatin-BCNU therapy and may be a major cause of pulmonary drug injury following this regimen.Implications: Strategies aimed at more uniform drug exposure or selective neutralization of chlorethylisocyanate, one of the two major hydrolysis products of BCNU, might reduce the incidence of acute lung injury following this regimen without major compromise of antitumor effect. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to define the maximal tolerated dose (MTD), extramedullary toxicities, and pharmacokinetics of docetaxel combined with high-dose melphalan and carboplatin with autologous hematopoietic progenitor cell support. Fifty-nine patients with advanced refractory malignancy (32 breast cancer, 10 non-Hodgkin lymphoma, 6 germ cell tumors, 4 Hodgkin disease, 4 ovarian cancer, 2 sarcoma, and 1 unknown primary adenocarcinoma) with a median of 3 prior chemotherapy regimens and a median of 3 organs involved were enrolled. Treatment included docetaxel (150–550 mg/m2 infused over 2 hours on day −6), melphalan (150–165 mg/m2 infused over 15 minutes from day −5 to −3), and carboplatin (1000-1300 mg/m2 as a 72-hour continuous infusion from day −5). Five patients died from direct regimen-related organ toxicity (2 capillary leak syndrome, 2 enterocolitis, and 1 hepatic toxicity), and 1 additional patient died from pulmonary aspergillosis. The docetaxel MTD was defined as 400 mg/m2, combined with melphalan (150 mg/m2) and carboplatin (1000 mg/m2). The MTD cohort was expanded to enroll a total of 26 patients, 1 of whom died from toxic enterocolitis. The remaining 25 patients presented the following extramedullary toxicity profile, which was manageable and largely reversible: stomatitis, myoarthralgias, peripheral neuropathy, gastrointestinal and cutaneous toxicities, and syndrome of inappropriate antidiuretic hormone secretion. Docetaxel exhibited linear pharmacokinetics in the dose range tested (150–550 mg/m2). Pharmacodynamic correlations were noted between the docetaxel area under the curve and peripheral neuropathy or stomatitis. The response rate among 38 patients with measurable disease was 95%, with 47% complete responses. At a median follow-up of 26 months (range, 7–72 months), the 3-year event-free survival and overall survival were 26% and 36%, respectively. In conclusion, a 4-fold dose escalation of docetaxel, combined with melphalan and carboplatin, is feasible with autologous hematopoietic progenitor cell support. The notable activity of this regimen in treatment-refractory patients warrants its further evaluation. [Copyright &y& Elsevier]