Cyclophosphamide Treatment of MS: current therapeutic approaches and treatment regimens.
Cyclophosphamide is an alkylating agent with cytotoxic effects, which is widely used for treatment of various types of malignancies including breast cancer, leukaemia and lymphoma. It is a pro-drug that requires hepatic activation in order to be cytotoxic.
Phosphoramide mustard and acrolein are formed following hepatic and cellular activation. Phosphoramide mustard is the active alkylating moiety responsible for the cytotoxic effects of cyclophosphamide, it forms intra- and interstrand DNA-DNA cross links, which are responsible for the inactivation of the DNA and hence, prevents cell replication. Acrolein binds to proteins, but does not contribute to the anti-tumour effects. Acrolein is toxic to the bladder and is associated with the development of haemorrhagic cystitis.
Cyclophosphamide has potent immunosupressive effects and suppresses both cell-mediated and humoral immunity and is known to cross the blood-brain barrier. It causes lymphopenia (involving both T-cells and B-cells) and has selective suppression of B-lymphocyte activity and decreases immunoglobulin secretion. The immunosuppressive properties of cyclophosphamide have led to its use for the treatment of immune-mediated inflammatory nonmalignant diseases such as lupus nephritis, vasculitis and immune-mediated neuropathies. (1-3) Cyclophosphamide was initially tested in multiple sclerosis (MS) over 30 years ago based on the hypothesis that MS is an inflammatory, cell-mediated, autoimmune disease. (4-6) With a better understanding of the inflammatory and degenerative components of MS, including the use of magnetic resonance imaging (MRI), there is now a clearer consensus of the MS patient populations that are appropriate to treat with cyclophosphamide with little evidence to support its use in later stages of progressive disease with no inflammatory component. (7) Although cyclophospamide has been widely used in MS, because it is not under patent, the pharmaceutical industry has not supported the necessary studies required for formal FDA approval of it. This situation is analogous to the use of intravenous steroids for the treatment of MS, another commonly used drug that does not have formal FDA approval.
Efficacy of Cyclophosphamide in MS in Initial Studies (1966-1999)
The use of cyclophosphamide in MS began in 1966 when Aimard et al described halting progression of the disease in a patient treated with it. (8) A detailed table of studies of cyclophosphamide in MS has been published. (9) In 1967, Girard et al (10) treated 30 patients with intravenous cyclophosphamide (200 mg/day for 4-6 weeks) and reported 50% of the patients were improved or stable at 2 years.
Hommes11 treated 32 patients with chronic progressive MS with high-dose cyclophosphamide plus prednisone for 20 days to induce leukopenia and found that most patients improved, some dramatically, especially those with shorter disease duration.
The first randomized controlled trial of cyclophosphamide in MS was reported in 1983, when 58 patients with progressive MS were treated with intravenous cyclophosphamide (400-500 mg/day to induce a leucopenia of 2000/[mm.sup.3]) plus adreno-corticotropic hormone (ACTH) versus ACTH alone versus plasma exchange/ACTH/oral cyclophosphamide. 12 Eighty per cent (16/20) of patients treated with intravenous cyclophosphamide were improved or stabilized at 12 months compared with 50% (9/18) in the plasma-exchange group and only 20% (2/20) in the group treated with ACTH alone.
Follow up of patients treated, demonstrated that by 18 months most patients began progressing again. This led to the Northeast Cooperative Multiple Sclerosis Treatment Group (13) which tested the effect of different induction regimens and the effect of chronic booster therapy in a fashion analogous to lupus nephritis protocols. A randomized trial of 256 patients received intravenous cyclophosphamide/ ACTH according to the published article, or a modified induction regimen with or without every-other-month intravenous pulses. There were no differences in stabilization between the two induction regimens. However, patients who received maintenance boosters had a significant delay in disease progression. Also, there was a significant age effect of the boosters: 40% of patients 18-40 years of age were stabilized or improved whereas, this was observed in only 14% of older patients. However, not all patients responded. Subgroup analysis revealed a poor prognosis at 12 months for patients with primary progressive MS, with over 55% failing compared with 41% of secondary progressive patients. Patients with recent onset of progression responded better to boosters (P=0.02) than those with progressive disease for a duration of more than 7 years. The Northeast Cooperative Treatment Group led to current protocols in which cyclophosphamide pulses are given on an outpatient basis. The subgroup analysis helped explain two studies which did not show an effect of cyclophosphamide in progressive MS. (14,15) The Canadian Cooperative Study randomly assigned 168 patients with progressive MS to intravenous cyclophosphamide/ oral prednisone versus plasma exchange, versus oral placebo plus sham exchange; no differences in disease progression were observed. This discrepancy appears related to two factors, the dosing regimens used, and more importantly, the type of patients treated. It appears that the Canadian study treated patients in later stages of progressive MS when, as we now know, MS is least responsive to anti-inflammatory therapy. This is best illustrated by studies with alemtuzumab, a powerful immunosuppressant, which did not affect progression given late in the course of the disease. (16) Of note, these studies were performed prior to the advent of MRI imaging.
In 1999, Gobbini et al reported the first MRI-based study of cyclophosphamide. (17) In this study, five relapsing-remitting patients refractory to interferon (IFN) were treated with monthly intravenous cyclophosphamide pulses (1000 mg/[m.sup.2]), and followed with monthly MRI and clinical evaluations for a mean of 28 months. All patients showed rapid reduction in contrast-enhancing lesion frequency and three patients had a decrease in T2 lesion load in the first 5 months of therapy. This was a crucial study that directly showed the effect of cyclophosphamide on inflammation in the brain and introduced the concept of second-line therapy for patients not responding to first-line immunomodulatory therapy.
In 1997, Weinstock-Guttman reported an open-label series of 17 patients with fulminant MS, defined as a deterioration of >1.5 Expanded Disability Status Scale (EDSS) points for more than 3 months, who were treated with intravenous cyclophosphamide (18) After 2 years, 69% of patients were stable or improved. In 1999, Hohol et al reported an open-label observational study of 95 patients with progressive MS treated with monthly pulses of cyclophosphamide and found that at 12 months, 80% of patients were stable or improved. (19)
Cyclophosphamide as Second-Line Therapy and Combination Therapy
In 2001, Khan et al (20) reported an open-label study of intravenous cyclophosphamide given monthly to 14 patients with rapidly deteriorating relapsing-remitting MS defined as >3 point worsening in EDSS score in the prior 12 months, despite immunomodulating therapy and intravenous steroids. Treatment stabilized or improved EDDS scores and no relapses were reported.
In 2003, Perini (21) reported an open-label study of 24 patients with clinically active/refractory MS treated with monthly intravenous cyclophosphamide/steroids for 1 year and then on alternate months for a second year. They found significant improvement in EDSS, relapse rate and MRI measures. In 2004, Zephir (22) reported a retrospective open-label review of 362 patients with secondary progressive MS and 128 patients with primary progressive MS, given 12monthly pulses of intravenous cyclophosphamide. They reported that the EDSS score stabilized or improved at Month 12 in 78.6% of patients with secondary progressive MS and in 73.5% of patients with primary progressive MS, and like the Northeast Cooperative Treatment Group, a shorter progressive disease course predicted response to therapy.
In 2004, the first combination therapy study of cyclophosphamide was reported by Patti. (23) Ten patients with frequent and severe attacks despite interferon-beta (IFNB) therapy, were given monthly intravenous cyclophosphamide in addition to the IFNB. The study showed significant reduction in the number of relapses, EDSS score and number of T2 lesions and these benefits were maintained for 36 months after the cyclophosphamide was discontinued.
In 2005, our group reported an MRI-based, single-blinded, randomized combination study (24) in which 59 relapsing-remitting MS patients with continued disease activity on IFNB received 3 days of intravenous methylprednisolone (MP) followed by 6- monthly treatments with either cyclophosphamide (800 mg/[m.sup.2]) plus intravenous MP or MP alone while remaining on IFNB. Patients were followed for an additional 18-months' post-infusion phase in which all received IFNB monotherapy. There was a significant decrease in the number of contrast-enhancing lesions in the group that received cyclophosphamide versus the intravenous steroid group at 3 months (P=0.01), 6 months (P=0.04) and 12 months (P=0.02). The clinical end-point time to treatment failure in the group receiving cyclophosphamide was significantly delayed (P=0.02) compared with the MP group. This study demonstrated the superiority of pulse cyclophosphamide versus pulse methylprednisolone in both clinical and MRI effects given in combination with IFNB.
Very High-Dose Cyclophosphamide for the Treatment of MS
With the advent of more aggressive forms of immunosuppression being used in MS, investigators have treated active, treatment refractive MS with higher doses of cyclophosphamide, given as an induction regimen. In 2006, Gladstone et al reported an open-label study in which cyclophosphamide 200 mg/kg over 4 days was given to 12 patients with treatment-refractory MS patients. (25) The study showed significant stability of disease and improved in quality of life after 15 months.
Investigators at Johns Hopkins University have treated nine active/refractory relapsing-remitting MS patients with very high doses of cyclophosphamide (termed, HiCy) to assess safety, tolerability, and clinical efficacy. (26) Patients were required to have two or more Gadolinium (Gd)-enhancing lesions on each of two pre-treatment MRIs, at least one clinical exacerbation in the 12 months prior to treatment or sustained increase of 1.0 or more on the EDSS in the preceding year. Patients received 50 mg/kg/day of intravenous cyclophosphamide for 4 consecutive days, followed by 5 mg/kg/day of granulocyte colony stimulating (GCS) factor, 6 days after completion of high-dose cyclophosphamide, until the absolute neutrophil count exceeded 1.0 x [10.sup.9] cells/L for 2 consecutive days. Patients were followed for a mean of 23 months. Eight patients had failed conventional therapy and one was treatment naive. The medium age at entry was 29 years. All patients developed transient total or near total pancytopenia, followed by haematopoietic recovery in 10-17 days, stimulated by GCS factor. There were no deaths or unexpected serious adverse events. There was a significant reduction in disability EDSS at follow up (2.11 [+ or -] 1.97) and an 81.4% reduction of Gd-enhancing lesions. The two pre-treatment scans were (6.5 [+ or -] 2.1 to 1.2 [+ or -] 2.3). Two patients required rescue treatment with other immunomodulatory therapy during the study due to MS exacerbation. The authors concluded that this immunoablative regimen of cyclophosphamide for patients with aggressive MS was safe, worthy of further study and may be an alternative to bone marrow transplantation.
Cyclophosphamide for the Treatment of Paediatric MS
Cyclophosphamide has also been used for the treatment of children with MS. In a review of the experience at several centres (27,20) children with worsening on the EDSS and/or multiple relapses were treated with one of three cyclophosphamide regimens:
1) Induction therapy alone.
2) Induction therapy with pulse maintenance therapy.
3) Pulse maintenance therapy alone.
Treatment resulted in a reduction in relapse rate and stabilization of disability scores assessed 1 year after treatment initiation in the majority of children and longer follow up was available for most cases. Cyclophosphamide was well tolerated in most patients although side-effects included vomiting, transient alopecia, osteoporosis, and amenorrhea.
One patient developed bladder carcinoma that was successfully treated. The authors conclude that cyclophosphamide is an option for the treatment of children with aggressive MS refractory to first-line therapies.
Cyclophosphamide as Initial Induction Therapy in MS
Because current disease-modifying agents are only partially effective, physicians have begun to use protocols in which 'induction' therapy with a strong immunosuppressant is given to patients felt to be at risk for more aggressive disease followed by conventional immunomodulatory treatment. Trials using mitoxantrone have reported positive results (28) and similar approaches have been reported for cyclophosphamide. (29) Active relapsing-remitting MS patients (>1 relapse in the prior 12 months and >1 Gd+ MRI lesion) were randomized to receive monthly cyclophosphamide designed to induce a leucopenia below 1000 x [mm.sup.3] plus methylprednisolone (MP) 1 g for 12 months followed by IFNB for a further 12 months; versus IFN for 2 years. The annual relapse rate was reduced from 1.9 to 0.1 at Year 1 and Year 2 in the cyclophosphamide group versus 0.5 in the interferon group (P=0.02); relapse-free patients at the second year was 80% in the cyclophosphamide group versus 40% in the IFN group (P=0.024); and the percentage of patients without Gd+ MRI lesions at 24 months was 90% in the cyclophosphamide group versus 54% in the IFN group-2 (P=0.04). No serious adverse events were observed during follow up. This study supports the concept of using cyclophospha-mide as an induction treatment for improving the impact of IFN over time. Perumal reported a study on the use of cyclophosphamide as the initial therapy in clinically active relapsing MS.30 None of the patients had received immunomodulatory therapy prior to cyclophosphamide treatment. All patients had experienced at least two relapses in the year prior to therapy. Twenty-six patients received monthly intravenous cyclophosphamide for 6 months followed by initiation of therapy with immunomodulatory therapy. At Year 1, the mean EDSS, relapse rate, and Gd-enhancing per patient at baseline were reduced from 3.61 to 2.22, 3.42 to 0.77 and 3.55 to 0.33 respectively. Mean percentage brain volume change at Year 1 was -2.37%. These studies demonstrate that cyclophosphamide may be used as initial therapy in relapsing-remitting MS patients.
Safety Profile and Role Comparison of Cyclophosphamide versus other Immunosuppressive Regimens
Cyclophosphamide was the first strong immunosuppressive treatment developed for MS with demonstrated efficacy. Presently, the approach of general immunosuppression or the use of drugs that affect major components of the immune system in MS has become widespread. Multiple drugs (both oral and intravenous) are now available and/or are being developed which have shown efficacy including general immunosuppressant drugs such as mitoxantrone, alemtuzumab, fingolimid, laquinimod, cladribrine and drugs which affect major components of the immune system such as natalizumab (T-cell trafficking) and rituximab (B-cell depletion). The clinician is confronted with the dilemma of which drug to use and when. The determining factors are efficacy, safety and ease of administration. There have been studies comparing cyclophosphamide versus mitoxantrone which did not show major differences between the two drugs, (31,32) but no other direct comparisons between cyclophosphamide and other regimens. The side-effects and toxicity of cyclophosphamide are well documented and are shown in Table 1. Because of potential effects on fertility both in men and women, some MS centres suggest sperm cryopreservation or ovarian protection (with hormones) before cyclophosphamide treatment in appropriate patients. It can be given for a longer time than mitoxantrone, which is limited by cardiac toxicity.
The risk of malignancy increases with cyclophosphamide dosage and a cumulative dose of greater than 80-100 g is not recommended (approximately 50 intravenous doses at 1000 mg/[m.sup.2]). Natalizumab is much easier to administer than cyclophosphamide, appears to have similar efficacy, and the major side-effect appears to be the risk of progressive multifocal leukoencephalopathy.
Immunological Effects of Cyclophosphamide in MS
In a paper by Paterson's group in 1969, cyclophosphamide was one of the first drugs shown to be effective in experimental allergic encephalitis, the animal model of MS, published in the journal Science. (33) Since then, many studies have found that cyclophosphamide is not simply a general immunosuppressant, but has selective effects on the immune system, effects with appear to be related to its beneficial effects in MS. (34,37) Cyclophosphamide increases Th2-type responses by inducing increased levels of IL-4, IL-5, and IL-10 and additionally, increases transforming growth factor beta (TGF-[beta]), a Th3 cytokine that is important for regulatory T-cells (Tregs). Cyclophosphamide also causes a decrease in IFN gamma (IFN[gamma]) and IL-12 secretion by monocytes. (38,39) The IL-12 decrease was found to be linked to its clinical effectiveness (40-42) and with a better understanding of immune networks (43) it is likely that the effects of cyclophosphamide on IL-12 were linked to effects on IL-23 and IL-17.
Cyclophosphamide may lead to an eosinophilia, and the level of eosinophils may be linked to its effectiveness. (44) Parasitic infections, which also are associated with eosinophils appear to benefit MS. (45) Cyclophosphamide reverses the increased (IFN[gamma]) production by CD8+ T-cells and increases the percentage of CCR4+ T-cells that produce high levels of IL-4 and decreases interferon gamma producing CCR5+ and CXCR 3+ CD8+T-cells. (46) Because cyclophosphamide crosses the blood-brain barrier, it may have a local CNS anti-inflammatory effect and early studies suggested an effect on increased CSF IgG. (47-50) It has recently been shown that depletion of B-cells by anti-CD20 antibody has a marked effect in decreasing MS relapses, perhaps by affecting T-cells through the antigen presenting activity of B-cells. Thus another mode of action immunologically of cyclophosphamide could relate to its effect on B-cells.
The role of inflammation in MS and the effectiveness of immune modulation in suppressing inflammation and positively affecting the clinical course of MS is now established. Cyclophosphamide is one of the first drugs to demonstrate this basic feature about MS. The major unanswered questions in MS relate to understanding and treatment of progressive forms and the degree to which early suppression of inflammation with drugs such as cyclophosphamide will prevent the progressive phase. The group of MS patients that will benefit most from anti-inflammatory therapy such as cyclophosphamide are younger patients between 18-40 years, with active disease (Gd-enhancing lesions on MRI and/or relapses in the year prior to therapy) and rapidly progressing disease course with less than 2 years in the progressive phase (Table 2). Although anti-inflammatory drugs with less side-effects than cyclophosphamide are being developed, presently, cyclophosphamide still has a role in the treatment of selected cases of MS. Its relatively low cost compared with other drugs may also be a factor in its use in the future.
* Cyclophosphamide has selective effects on the immune system, decreasing inflammatory cytokines and increasing anti-inflammatory cytokine.
* Cyclophosphamide affects B-cell function.
* Toxic effects on the bladder and the risk of malignancy prevent widespread cyclophosphamide use in early MS.
* Cyclophosphamide is indicated for patients with active inflammatory MS in response to first line immunomodulatory therapy.
* Cyclophosphamide is being investigated as induction therapy.
Received: 8 September 2009
Accepted: 12 January 2010
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AS Elkhalifa, HL Weiner
Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Address for Correspondence:
Howard L Weiner, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, HIM 720, Boston, MA 02115, USA
Tel: +1 617 525 5300
Fax: +1 617 525 5252
Table 1: Adverse effects of cyclophosphamide therapy * Nausea * Alopecia * Menstrual disorders and infertility * Leucopenia and infection * Bladder toxicity * Risk of cancer Table 2: Factors associated with a response to cyclophosphamide in people with MS * Rapidly progressive course * Gd+ lesions on MRI * Relapses in the year prior to therapy * Less than 2 years in progressive phase * Younger age (18-40 years)
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|Author:||Elkhalifa, A.S.; Weiner, H.L.|
|Publication:||The International MS Journal|
|Date:||Mar 1, 2010|
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