Amifostine (WR-2721), a cytoprotective agent during high-dose cyclophosphamide treatment of non-Hodgkin's lymphomas: a phase II study

Abstract

Clinical trials indicate that amifostine may confer protection on various normal tissues without attenuating anti-tumor response. When administered prior to chemotherapy or radiotherapy, it may provide a broad spectrum of cytoprotection including against alkylating drugs. The mechanism of protection resides in the metabolism at normal tissue site by membrane-bound alkaline phosphatase. Toxicity of this drug is moderate with hypotension, nausea and vomiting, and hypocalcemia being observed. We report a phase II study using amifostine as a protective drug against high-dose cyclophosphamide (HDCY) (7 g/m 2 ), used to mobilize peripheral blood progenitor cells (PBPC) and to reduce tumor burden. We enrolled 29 patients, 22 (75.9%) affected by aggressive and 7 (24.1%) by indolent non-Hodgkin's lymphoma (NHL), who were submitted to 58 infusions of amifostine and compared them with a historical group (33 patients) affected by aggressive NHL and treated with VACOP-B followed by HDCY. The most important results in favor of amifostine were the reduction of intensity of cardiac, pulmonary and hepatic toxicity, and a significant reduction of frequency and severity of mucositis (P = 0.04). None of the 29 patients died in the protected group, while in the historical group 2/33 patients died because of cardiac or pulmonary toxicity and 2 patients stopped therapy due to toxicity. Amifostine did not prevent the aplastic phase following HDCY. PBPC collection and hematological recovery were adequate in both groups. The number of CFU-GM (colony-forming units-granulocyte/macrophage) colonies and mononuclear cells in the apheresis products was significantly higher in the amifostine group (P = 0.02 and 0.01, respectively). Side effects were mild and easily controlled. We conclude that amifostine protection should be useful in HDCY to protect normal tissues, with acceptable side effects.

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation

“…It may be that reductions in supportive care may only be demonstrable when amifostine is used in combination with regimens associated with more prolonged and/or severe gastrointestinal toxicity, for example, melphalan 220 mg/m 2 or multi-agent high-dose chemotherapeutic regimens such as HD-VIC 9,20 Work undertaken combining amifostine pre-and posttreatment with carboplatin in patients with various cancers has demonstrated a reduction in dose-limiting thrombocytopenia despite enhanced drug delivery 31,32 Likewise, the severity and duration of neutropenia secondary to cyclophosphamide can be ameliorated by amifostine. 17 These effects would appear to be due principally to the ability of amifostine to protect haemopoietic progenitors from a range of chemotherapeutic agents, as shown by in vitro clonogenic assays 17,33,34 and further supported by engraftment data from a randomised trial of in vitro amifostine in the context of 4-HC purged bone marrow prior to transplantation. 35 This being the case, it is not surprising that we saw no differences in engraftment times or subsequent blood product support required when using myeloablative doses of melphalan as haemopoietic reconstitution was derived in both trial arms from reinfused progenitors that had not been exposed to conditioning chemotherapy.…”

“…9 Amifostine is a radioprotectant pro-drug that upon activation via dephosphorylation confers protection to normal but not malignant cells against oxygen-based radicals and electrophilic reactive drugs such as alkylator (nitrogen mustard, cyclophosphamide, melphalan) and organoplatinum anticancer drugs. [10][11][12][13][14][15][16][17] In animal models amifostine produces a significant increase in resistance to haemopoietic injury from alkylating agents and the nephrotoxicity of cisplatin, without altering antitumour activity. 10,14,18 Laboratory data suggest that the mechanism of amifostine's selective protection is related to its preferential uptake in normal vs malignant tissues.…”

Oral Mucositis Complicating Chemotherapy and/or Radiotherapy: Options for Prevention and Treatment

“…A series of clinical trials have reported on mucosaprotective effects of subcutaneous dosages up to 500 mg and on intravenous use at doses up to 740 mg/m 2 . [180][181][182][183][184][185][186][187][188][189] Side effects, mostly nausea and hypotension, seem to be more pronounced at higher doses and upon intravenous use, whereas, the optimal mucosaprotectant dose and route of administration remains to be defined. Studies evaluating the prophylactic use of amifostine during radiotherapy have uniformly reported a reduction of the incidence and severity of oral mucositis, but produced inconsistent results concerning the tolerability of the substanceregardless of its dosage and route of administration.…”

Use of transfer factor in immunosuppressed surgical patients

“…Statistical analysis of these variations was very significant (Table 2). the schedules used to be interrupted, which compromises treatment results [10][11][12][13][14][15][16][17][18][19][20] .…”