MDS, טיפול ב- TNF

שלום ד"ר בהמשך לשאלותי בנושא ה- MDS מה- 9/6, האם ידוע לך על יעילות הטיפול ב - TNF או אנטי TNF (כמו - pentoxifylline - Enbrel)ושילובים שונים עם אמיפוסטין ו/או תלידומיד למשל ?

הרעיון שמאחורי מתן TNF, כמו מתן ATG, הוא במקרים של MDS היפופלסטי שבהם יתכן שמדובר ב- MDS על רקע אימוני. מה שתארת אצל אביך לא נראה שייך לסוג זה של MDS. מכל מקום, הנסיון בטיפולים מסוג זה מועט ואנקדוטלי עדיין, ואיני יכול להתייחס לכך יותר מאשר כך. קרא והתרשם בעצמך. A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome. Maciejewski JP, Ristiano AM, Sloand EM, Wisch L, Geller N, Barrett JA, Young NS. Hematology Branch and Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. [email protected] Laboratory observations suggest that, in some myelodysplastic syndromes (MDS), immune mechanisms may contribute to the impaired blood cell production. Tumor necrosis factor alpha (TNF-alpha), a potent inhibitor of haematopoiesis, has been hypothesized to mediate suppressive effects in MDS: TNF-alpha levels are elevated and correlated with marrow apoptosis and cytopenia. Inhibition of TNF-alpha production using the soluble TNF receptor (Enbrel) has been successful in rheumatoid arthritis, and we have now applied the same principle to MDS. We determined spontaneous TNF-alpha production by marrow cells in MDS; TNF-alpha production was elevated (> mean + 2 x SD of controls) in > 1/3 of patients, but did not correlate with clinical parameters. Sixteen patients participated in a 3-month pilot study of Enbrel. The drug was well tolerated and 15 patients were evaluable. Of these, one became temporarily (14 weeks) transfusion independent. In another patient, absolute neutrophil count (ANC) rose from 0.5 x 10(9)/l to 0.84 x 10(9)/l. Serious infections were seen in two out of six neutropenic patients. Progression to refractory anaemia with excess blasts in transformation (RAEBt) or leukaemia was observed in three patients. When the effects of Enbrel on haematopoietic colony formation were studied, no significant increase was seen in MDS and there was no correlation with TNF-alpha levels. Although anti-TNF therapy with Enbrel was well tolerated at the dosages used in MDS, its efficacy as a single agent appears low *************************************************************** Treatment of myelodysplastic syndrome with agents interfering with inhibitory cytokines. Greenberg P. VA Palo Alto Health Care System and Stanford University Medical Centre, CA 94305, USA. [email protected] Results of these trials provide evidence for biological activity and some clinical efficacy of agents potentially blocking inhibitory cytokines in patients with MDS. However, given the limited responses, it appears that factors additional to TNFalpha inhibitory activity contribute to the development of cytopenias in these patients. Further studies are warranted using anti-TNFalpha/anti-inhibitory cytokine approaches, either alone or in combination with other agents, capable of abrogating the effects of additional inhibitory mechanisms in MDS. *************************************************** Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study. Deeg HJ, Gotlib J, Beckham C, Dugan K, Holmberg L, Schubert M, Appelbaum F, Greenberg P. Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Blockade of tumor necrosis factor (TNF)alpha by a soluble TNF receptor fusion protein (etanercept; Enbrel) improved in vitro hemopoiesis from the marrow of patients with myelodysplastic syndrome (MDS). Therefore, we enrolled 14 MDS patients (4 RA, 2 RARS, 6 RAEB, 2 CMML), 44-80 (median 60) years old, in a pilot trial. Etanercept, 25 mg, was given twice a week s.c. for 16 weeks (increased to three times a week if no response at 8 weeks). Among 12 evaluable patients, four had rises in hemoglobin by 1-1.5 gm/dl (three) or decreased transfusion requirements (one). Two patients had increased platelet counts (54% and 73%), and two increased neutrophils (63% and 120%). Baseline TNFalpha levels, determined in all patients, did not correlate with responses. Among eight marrows available for sequential in vitro assays, four showed increases in CFU-GM of 1.5- to 5-fold at 8 weeks, whereas three showed 3- to 10-fold decrements relative to baseline. Thus, etanercept treatment resulted in moderate improvements of cytopenias in some patients, while cell counts declined in others. Additional trials are needed to evaluate its clinical efficacy in MDS