High Dose Cyclophosphamide Treatment for Autoimmune Disorders

Abstract

High-dose cyclophosphamide (200 mg/kg) was initially developed as a conditioning regimen for allogeneic bone marrow transplantation. Recently, high-dose cyclophosphamide without bone marrow transplantation has been employed as a method to induce durable treatment-free remissions in severe aplastic anemia and a variety of other severe autoimmune disorders. The premise underlying this approach is that high-dose cyclophosphamide is maximally immunosuppressive, but not myeloablative. Early hematopoietic stem cells are spared the cytotoxicity of cyclophosphamide because of their high levels of aldehyde dehydrogenase, an enzyme that confers resistance to the drug. Conversely, autoimmune effector cells (T cells, B cells, and NK cells) are exquisitely sensitive to high-dose cyclophosphamide because of their relatively low levels of aldehyde dehydrogenase. Intensive investigation is underway to determine which autoimmune disorders will most benefit and where in the natural history of these diseases to employ this rapidly developing therapy.KEY WORDS: high dose cyclophosphamide, autoimmune disease, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplantation DOMAINS: autoimmunity, hematology, bone marrow failure, pharmacology, aplastic anemia, bone marrow transplantation.

Covalent DNA–Protein Cross-Linking by Phosphoramide Mustard and Nornitrogen Mustard in Human Cells

“…Further studies will establish whether these differences in specificity could contribute to different biological outcomes of DEB (known carcinogen) 51–53 and cyclophosphamide (useful antitumor agent). 14–16 …”

“…14–16 Under physiological conditions, PM spontaneously dephosphoramidates to form another DNA alkylating agent, nornitrogen mustard (NOR) (Scheme 1). 17–19 Both PM and NOR can modify N-7-guanine of DNA to yield N-(2-chloroethyl)-N-[2-(7-guaninyl)ethyl] amine, N-(2-hydroxyethyl)-N-[2-(7-guaninyl)ethyl] amine, and N,N - bis -[2-(7-guaninyl)ethyl] amine adducts, 17–19 and also produce covalent DNA-protein conjugates (Scheme 1).…”

High-dose chemotherapy and multiple sclerosis

“…In 2002, we published the first report of HDC without stem cell rescue for an auto-immune neurologic illness: chronic inflammatory-demyelinating polyneuropathy and updated that experience in 2005 and 2007 [42,43]. We and others have shown HDC without stem cell rescue can decrease disease activity and improve quality of life in numerous immune-mediated illnesses [44,45 • ,46,47]. In 2006, based on 13 patients, we published the first report showing HDC without stem cell rescue to be effective therapy in moderate to severe refractory MS [48].…”

Concise review: Hematopoietic stem cell transplantation to treat insulin-dependent diabetes mellitus

“…CY is referred to as a chemotherapy drug and has been classified as an "alkylating agent". After injection in the body, CY is transformed to 4-hydroperoxycyclophosphamide (4HC) and aldophosphamide (AP) in the liver (Brodsky, 2002). In cells which have high levels of aldehyde dehydrogenase (ALDH) like HSCs, AP is converted to a harmless substance (carboxyphosphamide) and these cells will not be affected.…”

“…However, in cells which have low levels of ALDH like autoimmune effector cells, AP is changed to phosphoramide mustard and will induce cell death. Most lymphocytes, T cells, B cells, and NK cells, when exposed to phosphoramide mustard, will die resulting in the depletion of autoreactive effector cells (Brodsky, 2002). After treatment with high-dose cyclophosphamide, patients are injected with autologous or allogeneic HSCs and monitored for the effects of transplantation.…”