Autotransplantation for advanced lymphoma and Hodgkin's disease followed by post-transplant rituxan/GM-CSF or radiotherapy and consolidation chemotherapy.

Disease relapse occurs in 50% or more of patients who are autografted for relapsed or refractory lymphoma (NHL) or Hodgkin's disease (HD). The administration of non-cross-resistant therapies during the post-transplant phase could possibly control residual disease and delay or prevent its progression. To test this approach, 55 patients with relapsed/refractory or high-risk NHL or relapsed/refractory HD were enrolled in the following protocol: stem cell mobilization: cyclophosphamide (4.5 g/m(2)) + etoposide (2.0 g/m(2)) followed by GM-CSF or G-CSF; high-dose therapy: gemcitabine (1.0 g/m(2)) on day -5, BCNU (300 mg/m(2)) + gemcitabine (1.0 g/m(2)) on day -2, melphalan (140 mg/m(2)) on day -1, blood stem cell infusion on day 0; post-transplant immunotherapy (B cell NHL): rituxan (375 mg/m(2)) weekly for 4 weeks + GM-CSF (250 microg thrice weekly) (weeks 4-8); post-transplant involved-field radiotherapy (HD): 30-40 Gy to pre-transplant areas of disease (weeks 4-8); post-transplant consolidation chemotherapy (all patients): dexamethasone (40 mg daily)/cyclophosphamide (300 mg/m(2)/day)/etoposide (30 mg/m(2)/day)/cisplatin (15 mg/m(2)/day) by continuous intravenous infusion for 4 days + gemcitabine (1.0 g/m(2), day 3) (months 3 + 9) alternating with dexamethasone/paclitaxel (135 mg/m(2))/cisplatin (75 mg/m(2)) (months 6 + 12). Of the 33 patients with B cell lymphoma, 14 had primary refractory disease (42%), 12 had relapsed disease (36%) and seven had high-risk disease in first CR (21%). For the entire group, the 2-year Kaplan-Meier event-free survival (EFS) and overall survival (OS) were 30% and 35%, respectively, while six of 33 patients (18%) died before day 100 from transplant-related complications. The rituxan/GM-CSF phase was well-tolerated by the 26 patients who were treated and led to radiographic responses in seven patients; an eighth patient with a blastic variant of mantle-cell lymphoma had clearance of marrow involvement after rituxan/GM-CSF. Of the 22 patients with relapsed/refractory HD (21 patients) or high-risk T cell lymphoblastic lymphoma (one patient), the 2-year Kaplan-Meier EFS and OS were 70% and 85%, respectively, while two of 22 patients (9%) died before day 100 from transplant-related complications. Eight patients received involved field radiation and seven had radiographic responses within the treatment fields. A total of 72 courses of post-transplant consolidation chemotherapy were administered to 26 of the 55 total patients. Transient grade 3-4 myelosuppression was common and one patient died from neutropenic sepsis, but no patients required an infusion of backup stem cells. After adjustment for known prognostic factors, the EFS for the cohort of HD patients was significantly better than the EFS for an historical cohort of HD patients autografted after BEAC (BCNU/etoposide/cytarabine/cyclophosphamide) without consolidation chemotherapy (P = 0.015). In conclusion, post-transplant consolidation therapy is feasible and well-tolerated for patients autografted for aggressive NHL and HD and may be associated with improved progression-free survival particularly for patients with HD.

Physiological control of alkylsulfatase synthesis in Pseudomonas aeruginosa: effects of glucose, glucose analogs, and sulfur.

Pseudomonas aeruginosa (isolated from soil) synthesizes an alkylsufatase allowing this bacterium to utilize sodium hexan-1-yl sulfate as a source of carbon and sulfur for growth. The formation of the enzyme was induced by this and by other (C4-C16) primary alkylsulfate esters as well as by some (C-8 and C-9) primary alkylsulfonates. Secondary (2-yl) alkylsulfate esters did not act as inducers. The induction of alkylsulfatase was markedly inhibited by L-cysteine, L-methionine, sodium sulfide, and by high (greater than 2mM) concentrations of D-glucose and other related monosaccharides. Similar inhibitory effects by four glucose analogs which will not support growth suggest that prior metabolism was not a requirement for glucose-mediated inhibition. The inhibition by D-glucose of the same inducible system in P. aeruginosa (PAO-57) supported this conclusion since this glucose transport-positive mutant is deficient in the further metabolism of the monosaccharide. At low (0.1-1.0 mM) concentrations, D-glucose or D-glucose 6-O-phosphate (20 mM) caused a marked enhancement of alkylsulfatase induction in the isolate. This novel enhancement was reproduced using P. aeruginosa strain PAO. However, both monosaccharides acted as potent inhibitors of alkylsulfatase formation occurring in mutant PAO-57 which, unlike the parent strain PAO, exhibits low glucose-6-phosphate dehydrogenase activity. These results suggest that D-glucose (0.1-1.0 mM) must be metabolized to enhance the synthesis of the enzyme.