Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone

Abstract

Thirty-five patients with myelodysplastic syndrome (MDS) were registered on protocol MDS 96-02 and were receiving continuous therapy with pentoxifylline 800 mg 3 times a day and ciprofloxacin 500 mg twice a day by mouth; dexamethasone was added to the regimen for the partial responders and the nonresponders after 12 weeks at a dose of 4 mg by mouth every morning for 4 weeks. Amifostine was administered intravenously 3 times a week at 3 dose levels (200 mg/M2, 300 mg/M2, and 400 mg/M2) to cohorts of 10 patients each. Therapy has been continued for 1 year in responders. Twenty-nine have completed at least 12 weeks of therapy and are available for response evaluation. Of the 21 men and 8 women (median age, 67 years), 20 had refractory anemia (RA), 3 had RA with ringed sideroblasts (RARS), 5 had RA with excess blasts (RAEB), and 1 had chronic myelomonocytic leukemia (CMMoL). Five had secondary MDS. No differences were noted in response rates among the 3 dose levels. Seven patients did not respond at all, and 22 showed an improvement in cytopenias (76%). Three had a triple lineage response, 10 had a double lineage response, and 9 had a single lineage response (8 of 9 in absolute neutrophil count [ANC] and 1 had more than a 50% reduction in packed red blood cell transfusions). Fifteen patients responded only after the addition of dexamethasone, whereas 7 responded before. When examined by lineage, 19 of 22 showed improved ANC, 11 of 22 demonstrated more than 50% reduction in blood transfusions, improved Hb levels, or both, and 7 of 22 showed improvement in platelet counts. Interestingly, the responses were frequently slow to appear, and continued improvement in counts was seen up to 12 months of therapy and beyond. This study supports the feasibility of treating patients with MDS with the unique approach of cytoprotection and anticytokine therapies as well as the principle that prolonged commitment to treatment is desirable when noncytotoxic agents are administered.

Digging deep into “dirty” drugs – modulation of the methylation machinery

“…The Anti-TNFα antibody infliximab and the TNFα-receptor fusion protein etanercept have been approved for clinical use in other entities (psoriasis, Crohn's disease, ulcerative colitis for infliximab, as well as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis for etanercept), and have also shown clinical activity in MDS (Deeg et al, 2002 ; Raza et al, 2004 ; Scott et al, 2010a , b ; Stasi et al, 2005 ). The xanthin derivative pentoxifylline, approved for intermittent claudication from peripheral artery disease, also reduces the level of various cytokines, including TNFα; clinical activity in MDS and AML has been demonstrated (Erikci et al, 2008 ; Kim et al, 2006 ; Raza et al, 2000a , b ).…”

Effects of cyclosporine on hematopoietic and immune functions in patients with hypoplastic myelodysplasia

“…35 Moreover, studies on mice lacking the Fas-receptor (Fas-R) or Fas-L have documented that Fas-L is one of the major effector molecules of CD4 ϩ Th1 and CD8 ϩ T lymphocytes. 36,37 Alternative therapies have been introduced in the past few years for patients with MDS, including antiapoptotic, 38 anticytokine, 39 and immunosuppressive regimens. 6,26 -31,40,41 Although antiapoptotic and anticytokine agents deserve further investigations, more convincing results have been accumulated in the past few years on the role of immunosuppressive agents, including antithymocyte globulin (ATG) and cyclosporine (CsA).…”

New Approaches to the Treatment of Myelodysplasia

“…However, an improvement in cytopenias was observed in 76% (22/29) of the patients. In addition, 86% (19/22) of the patients showed improvements in neutrophil counts, 32% (7/22) had improvement in thrombocytopenia, and 50% (11/22) had a >50% decrease in transfusion requirements [63]. These results suggest that the combination of cytoprotection and hematopoietic stimulation with amifostine to decrease apoptosis is a fertile avenue for continued investigation in the treatment of MDS.…”

“…Recent studies investigating the potential for added benefit when used in combinations appear promising [60][61][62][63]. Amifostine has been applied in combination with other antiapoptotic strategies using pentoxifylline, ciprofloxacin, and dexamethasone for the treatment of patients with MDS [63]. Pentoxifylline is a xanthine derivative that interferes with lipid-signaling pathways used by proapoptotic cytokines (e.g., IL-1β, TNF-α, transforming growth factor-β [TGF-β]) to reduce their activity.…”

“…Ciprofloxacin was added as a pharmacologic inhibitor of the hepatic metabolism of pentoxifylline, whereas dexamethasone was added to downregulate mRNA translation of TNF-α. Amifostine was administered intravenously at doses of 200, 300, and 400 mg/m 2 , three times weekly, to cohorts of 10 patients each [63]. Twentynine patients completed at least 12 weeks of treatment.…”