ALBERT

Beschreibung: Mucositis being an adverse effect of high-dose chemotherapy (hd CTx) may compromise results of peripheral blood stem cell transplantation (PBSCT). Keratinocyte growth factor can effectively decrease its severity and frequency. Here, the mucositis rate after BEAM hd CTx followed by auto-PBSCT was analyzed. A total of 50 patients (median age: 55 years, range; 19–70) with high-risk, refractory or relapsed lymphoma were included in a prospective analysis at our center, and mucositis was graded according to WHO. After BEAM-hd CTx, WHO grade 2 mucositis developed in 30%, grade 3 in 10% and grade 4 in 4%. Odds ratios (OR) for mucositis grade 2 or higher were increased to 2.1 (95% CI 0.6–6.7) for female sex, to 1.9 (CI 0.5–6.7) for higher pretreatment (〉8 CTx-cycles), and 3.1 (CI 0.9–10.5) with previous mucositis. We found no association for older age, lymphoma type (indolent vs. high-grade NHL/Hodgkin’s disease), previous radiotherapy, Karnofsky index, oral hygiene or leukopenia prior to auto-PBSCT. The OR for mucositis with parental nutrition was estimated with 2.2 (CI 0.6–7.7) and for opioid use with 8.7 (CI 2.2–33.7) (p=0.0025), both being directly influenced by the extend and severity of oral mucositis. As expected, myelosuppression was the main toxicity of hd-BEAM: WBC 〉1.000/ml were reached after a median of 10 days (range 7–15), platelets 〉20.000/ml after 11 days (range 7–45). The median numbers of red blood cell and platelet units transfused were 5 (range 1–21) and 4 (range 1–35), respectively. The event free survival at 6, 12 and 24 months was 81.9% (CI 71.2–92.6%), 70.5% (CI 57.3–83.6%), and 66% (CI 51.2–80.9%), and the overall survival 83.9% (CI 73.7–94.1%), 79.2% (CI 67.7–90.8%) and 79.2% (CI 67.7–90.8%), respectively. Subsequently, 10 lymphoma patients have been accrued in the follow-up study comparing palifermin to best supportive care (BSC) after hd-BEAM conditioning. All 5 patients receiving palifermin showed only WHO grad 1 mucositis, whereas in the control group one patient each had grade 1, 2 and 3 mucositis and 2 patients are still being treated. In conclusion, we found females, extensive pretreatment and previous mucositis as potential risk factors for the development of mucositis, the latter greatly influencing parental nutrition and opioid use. Although the incidence of grade 2–4 mucositis varies with different CTx-schedules and -intensity, it severely affects supportive measures. Decrease in its severity and duration will substantially reduce side-effects of PBSCT further.

Beschreibung: The conditions that control the migratory status of hematopoietic progenitor cells on extracellular matrix (ECM) and that decide whether a cell migrates or adheres are incompletely understood. We analyzed the migratory behavior of murine hematopoietic progenitor cells factor-dependent-cell-paterson (FDCP)-mix and purified lin−Sca1+ bone marrow cells on ECM. We found that migration on fibronectin (Fn) or laminin (Lam) becomes dependent on β1-integrins if a surface restraint force is introduced by tilting the ECM-coated culture vessels. Under these conditions, migration specifically occured on Fn and Lam, and was not detected on collagen IV-, hyaluronate-, or bovine serum albumin- coated surfaces. Migration depended on the continuous presence of hematopoietic cytokines interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF ), macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF ), or stem cell factor (SCF), whereas other cytokines, such as IL-8, macrophage inflammatory protein-1α, macrophage-chemotactic and activating factor, and erythropoietin resulted in very little or no migratory response. IL-3 induced migration was synergistically enhanced by other CSFs, but was completely inhibited by addition of transforming growth factor-β1. In contrast to firm local adhesion of previously cytokine depleted progenitors that was rapidly inducible within 1 hour after exposure to cytokines, preincubation on Fn matrix for 4 to 6 hours was required before cytokines could induce migration. A sudden increase of cytokine concentration reversibly inhibited migration and induced a fully adhesive state; this effect could be prolonged by consecutive stimulation with heterologous cytokines. Whereas cytokines activated resting progenitor cells to migrate on ECM, cell migration speed was regulated by Fn concentration. These results indicate that β1-integrin–mediated progenitor cell adhesion and migration are differentially regulated by external stimuli and suggest that this regulation corresponds to different activation states of β1-integrins in hematopoietic progenitor cells.