UZ Leuven

CD34+ marrow progenitors from MDS patients with high levels of intramedullary apoptosis have reduced expression of α4β1 and α5β1 integrins. Delforge M, Raets V, Van Duppen V, Vandenberghe P, Boogaerts M. Leukemia 2005;19:57-63. Abstract: Excessive intramedullary apoptosis is central in the pathogenesis of myelodysplastic syndromes (MDS). Growth-inhibiting cytokines, the Fas/FasLigand pathway, and autoreactive cytotoxic T-lymphocytes have been identified to be important proapoptotic factors in MDS. In normal hematopoiesis, a4β1 and α5β1 integrin-mediated interactions between progenitors and fibronectin are critical for progenitor cell survival. In this study, we have used flow cytometry to quantify the expression levels of members of the β1 integrin family on CD34+ marrow progenitors in 27 untreated patients with MDS, three with s-AML, and 25 control subjects. In MDS, we observed that nonapoptotic progenitors significantly downregulate cell surface expression levels of α4 and β1 integrin chains compared with healthy controls. Downregulation of α4, β1, and also α5 was present in MDS patients with ≥25% apoptotic progenitors, irrespective of their French, American, British subcategory. Reduced cell surface expression levels of a4, a5, and β1 did also correlate with decreased in vitro adhesiveness to fibronectin fragments. Therefore, our observations suggest that downregulation of a4β1 and a5β1 integrins on CD34+ progenitors could be a newly identified proapoptotic mechanism in MDS.

Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, Cornely OA, Bourque MR, Lupinacci RJ, Sable CA, DePauw BE. N Engl J Med 2004; 351:1391-402. Abstract: Background : Patients with persistent fever and neutropenia often receive empirical therapy with conventional or liposomal amphotericin B for the prevention and early treatment of invasive fungal infections. Caspofungin, a member of the new echinocandin class of compounds, may be an effective alternative that is better tolerated than amphotericin B. Methods In this randomized, double-blind, multinational trial, we assessed the efficacy and safety of caspofungin as compared with liposomal amphotericin B as empirical antifungal therapy. At study entry, patients were stratified according to risk and according to whether they had previously received antifungal prophylaxis. A successful outcome was defined as the fulfillment of all components of a five-part composite end point. Results : Efficacy was evaluated in 1095 patients (556 receiving caspofungin and 539 receiving liposomal amphotericin B). After adjustment for strata, the overall success rates were 33.9 percent for caspofungin and 33.7 percent for liposomal amphotericin B (95.2 percent confidence interval for the difference, –5.6 to 6.0 percent), fulfilling statistical criteria for the noninferiority of caspofungin. Among patients with baseline fungal infections, a higher proportion of those treated with caspofungin had a successful outcome (51.9 percent vs. 25.9 percent, P=0.04). The proportion of patients who survived at least seven days after therapy was greater in the caspofungin group (92.6 percent vs. 89.2 percent, P=0.05). Premature study discontinuation occurred less often in the caspofungin group than in the amphotericin B group (10.3 percent vs. 14.5 percent, P=0.03). The rates of breakthrough fungal infections and resolution of fever during neutropenia were similar in the two groups. Fewer patients who received caspofungin sustained a nephrotoxic effect (2.6 percent vs. 11.5 percent, P<0.001), an infusion-related event (35.1 percent vs. 51.6 percent, P<0.001), or a drug-related adverse event or discontinued therapy because of drug-related adverse events. Conclusions: Caspofungin is as effective as and generally better tolerated than liposomal amphotericin B when given as empirical antifungal therapy in patients with persistent fever and neutropenia.

A randomized multicenter comparison of CD34(+)-selected progenitor cells from blood vs. from bone marrow in recipients of HLA-identical allogeneic transplants for hematological malignancies. Cornelissen JJ, van der Holt B, Petersen EJ, Vindelov L, Russel CA, Hoglund M, Maertens J, Schouten HC, Braakman E, Steijaert MM, Zijlmans MJ, Slaper-Cortenbach I, Boogaerts MA, Lowenberg B, Verdonck LF. Exp Hematol 2003;31: 855-64. Abstract: Objective: Peripheral blood progenitor cells (PBPC) have been established as an alternative source of hematopoietic stem cells for allogeneic transplantation, but an increased incidence of both acute and chronic graft-vs-host disease (GVHD) has become apparent. We performed a prospective randomized trial comparing bone marrow transplantation (BMT) vs PBPC transplantation (PBPCT) using CD34+ selection for T-cell depletion (TCD) in both study arms. Patients and Methods: Between January 1996 and October 2000, 120 patients with a diagnosis of acute leukemia, myelodysplasia, multiple myeloma, or lymphoma were randomized to receive either filgrastim-mobilized PBPC or BM from HLA-identical sibling donors after standard high-dose chemoradiotherapy. Patient  characteristics did not differ between study arms. Results : Recipients of PBPC received more CD3+ T cells (median: 3.0 vs 2.0×105/kg, p<0.0001) and more CD34+ cells (median: 3.6 vs 0.9×106/kg, p<0.0001). Neutrophil and platelet recoveries occurred significantly faster after PBPCT. The cumulative incidence of acute GVHD grades II–IV was 37% after BMT vs 52% after PBPCT and was most significantly (p = 0.007) affected by the number of CD3+ T cells in the graft. Acute GVHD appeared strongly associated with increased treatment-related mortality (TRM) in a time-dependent analysis. Higher numbers of CD34+ cells were associated with less TRM. With a median follow-up of 37 months (range: 12–75), overall survival at 4 years from transplantation was 60% after BMT and 34% for recipients of PBPCT (p= 0.04), which difference was largely due to increased GVHD and TRM in PBPC recipients receiving Tcell dosages greater than 2×105/kg. Conclusion: Outcome following T cell–depleted PBPCT critically depends on the number of CD3+ T cells, whereby high T-cell numbers may blunt a favorable effect of higher CD34+ cell numbers.

Additional prognostic value of bone marrow histology in patients subclassified according to the international prognostic scoring system for myelodysplastic syndromes. Verburgh E, Achten R, Maes B, Hagemeijer A, Boogaerts M, De Wolf-Peeters C, Verhoef G.J ClinOncol 2003;21:273-282. Abstract: Purpose: The most recent and powerful prognostic instrument established for myelodysplastic syndromes (MDS) is the International Prognostic Scoring System (IPSS), which is primarily based on medullary blast cell count, number of cytopenias, and cytogenetics. Although this prognostic system has substantial predictive power in MDS, further refinement is necessary, especially as far as lower-risk patients are concerned. Histologic parameters, which have long proved to be associated with outcome, are promising candidates to improve the prognostic accuracy of the IPSS. Therefore, we assessed the additional predictive  power of the presence of abnormally localized immature precursors (ALIPs) and CD34 immunoreactivity in bone marrow (BM) biopsies of MDS patients. Patients and Methods: Cytogenetic, morphologic, and clinical data of 184 MDS patients, all from a single institution, were collected, with special emphasis on the determinants of the IPSS score. BM biopsies of 173 patients were analyzed for the presence of ALIP, and CD34 immunoreactivity was assessable in 119 patients. Forty-nine patients received intensive therapy. Results : The presence of ALIP and CD34 immunoreactivity significantly improved the prognostic value of the IPSS, with respect to overall as well as leukemia-free survival, in particular within the lower-risk categories. In contrast to the IPSS, both histologic parameters also were predictive of outcome within the group of intensively treated MDS patients. Conclusion: Our data confirm the importance of histopathologic evaluation in MDS and indicate that determining the presence of ALIP and an increase in CD34 immunostaining in addition to the IPSS score could lead to an improved prognostic subcategorization of MDS patients.

Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukaemia. Löwenberg B, Van Putten W, Theobald M, Gmür J, Verdonck L, Sonneveld P, Fey M, Schouten H, de Greef G, Ferrant A, Kovacsovics T, Gratwohl A, Daenen S, Huijgens P, Boogaerts M. N Engl J Med 2003;349:743-752. Abstract: Background Sensitization of leukemic cells with hematopoietic growth factors may enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML). Methods In a multicenter randomized trial, we assigned patients (age range, 18 to 60 years) with newly diagnosed AML to receive cytarabine plus idarubicin (cycle 1) and cytarabine plus amsacrin (cycle 2) with granulocyte colony-stimulating factor (G-CSF) (321 patients) or without G-CSF (319). GCSF was given concurrently with chemotherapy only. Idarubicin and amsacrin were given at the end of a cycle to allow the cell-cycle-dependent cytotoxicity of cytarabine in the context of G-CSF to have a greater effect. The effect of G-CSF on disease-free survival was assessed in all patients and in cytogenetically distinct prognostic subgroups. Results After induction chemotherapy, the rates of response were not significantly different in the two groups. After a median follow-up of 55 months, patients in complete remission after induction chemotherapy plus G-CSF had a higher rate of disease-free survival than patients who did not receive G-CSF (42 percent vs. 33 percent at four years, P=0.02), owing to a reduced probability of relapse (relative risk, 0.77; 95 percent confidence interval, 0.61 to 0.99; P=0.04). G-CSF did not significantly improve overall survival (P=0.16). Although G-CSF did not improve the outcome in the subgroup with an unfavorable prognosis, the 72 percent of patients with standard-risk AML benefited from GCSF therapy (overall survival at four years, 45 percent, as compared with 35 percent in the group that did not receive G-CSF [relative risk of death, 0.75; 95 percent confidence interval, 0.59 to 0.95; P=0.02]; disease-free survival, 45 percent vs. 33 percent [relative risk, 0.70]; 95 percent confidence interval, 0.55 to 0.90; P=0.006). Conclusions: Sensitization of leukemic cells with growth factors is a clinically applicable means of enhancing the efficacy of chemotherapy in patients with AML.

The value of Fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high risk myelodysplastic syndromes and elderly AML. Ossenkoppele G, Graveland W, Sonneveld P, Daenen S, Biesma D, Verdonck L, Schaafsma M, Westveer P, Peters G, Noordhuis P, Muus P, van de Holt B, Delforge M, Lowenberg B, and Verhoef G. Blood 2004;103: 2908-2913. Abstract: Fludarabine in addition to cytosine-arabinoside (ARA-C) increases the accumulation of ARA-C–5’- triphosphate (ARA-CTP), which is responsible for the cytotoxic effect in leukemic blasts. In a randomized phase 3 trial, patients with high-risk  yelodysplastic syndrome (MDS) (n = 91) or elderly patients with acute myeloid leukemia (AML) (n = 43) were randomized to receive 2 induction courses consisting of ARA-C (2 g/m2 days 1 through 5) and granulocyte colony-stimulating factor (G-CSF) (filgrastim, 5μg/ kg) during and after chemotherapy with or without fludarabine (25 mg/m2, days 1 through 5) (FLAG versus AG). Consolidation consisted of daunorubicin (45 mg/m2, days 1 through 3) and ARA-C (200 mg/m2, days 1 through 7). Complete remission (CR) rate following AG was 65% versus 71% with FLAG (P = .49). Overall survival (OS) at 24 months was 24% for AG treatment and 39% for FLAG (P = .32). Event-free survival (EFS) at 2 years was 10% and 19% (P = .31) for the AG and FLAG treatments, respectively. Platelet and granulocyte recovery times after the second cycle were prolonged in the FLAG treatment group. Grades 3 to 4 neurotoxicities were more often reported in the FLAG arm (14% versus 3%, P = .03), whereas no significant differences in other toxicities were observed. In a cohort of patients, the in vivo accumulation of ARA-CTP in leukemic cells was determined. Although ARA-CTP accumulation in leukemic cells after FLAG was enhanced, clinical outcome in terms of CR rate, OS, EFS, and  diseasefree survival (DFS) was not significantly improved by combining fludarabine with ARA-C.

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