Review Article

Lights and Shadows of Cyclophosphamide in the Treatment of Multiple Sclerosis

Table 1

Clinical studies of cy in the treatment of MS.

DateAuthorNo. of patientsType of MSRegimenComments and side effects

Study of cy in to treat the relapse of MS
1975Drachman et al.6Acute attacks4–5 mg/kg IV for 10 successive daysNo effect observed on recovery from relapse

Studies of cy in progressive MS
1966Aimard et al.1ProgressiveArrest of disease in progressive MS patients,
1967Girard et al.30Progressive200 mg/day IV for 4–6 weeks; (4–9 g total)50% improved or stable at 2 years
1969Millac and Miller16ProgressiveOral, 75–100 mg/dayToxicity associated with low white blood counts
1975Hommes et al.32Progressive100 mg qid + 50 mg prednisone bid (8 g total over 20 days)Stabilization in 69% of patients. Better results were found in patients with shorter duration of their disease
1980Hommes et al.39Progressive400 mg cy + 100 mg prednisone. 8 g totalStabilization in 69% of patients. Open label, uncontrolled
1981Theys et al.21Progressive6–8 g given over 3–4 weeksNo effect in patients with moderately advanced MS over 2 years
1983Hauser et al.20Progressive400–500 mg/day IV for 10–14 days + ACTH16/20 stabilized at 1 year versus 4/20 with ACTH and 9 out of 18 with plasma exchange regimen
1987Goodkin et al.27ProgressiveInpatient induction for 10–14 days with IV cy/ACTH or outpatient induction with 700 mg/m2 weekly for 6 weeks plus prednisoneMaintenance therapy of 700 mg/m2 every 2 months for 24 months. Stabilization in 59% of patients induced at 12 months versus 17% in nonrandomized controls
1987Myers et al.14ProgressiveMonthly therapy with 400–800 mg/m2 oral or IV escalating to 1200–2000 mg/m2 monthly; 5–13 doses given over 5–14 months to reduce B cell and CD4+ cells. With and without steroids3 improved, 9 unchanged, and 2 worsened
1987Siracusa et al.14ProgressiveShort course of intensive cy until WBC reached 30005 patients discontinued because of side effects. Patients stable, though not improved
1988Carter et al.164Progressive2-week IV cy/ACTH regimen81% improved or stable at 1 year. Reprogression in 69% of patients at mean of 17.6 months
1989Mauch et al.21Progressive8 mg/kg IV at 4-day intervals until lymphocyte count was half the initial value. (1.9 g average total dose)20/21 patients stable at 1 year versus 7/21 patients receiving ACTH
1989Canadian55Progressive1 g IV on alternate days up to 9 g + oral prednisoneNo difference versus placebo ( ) or plasma exchange regimen. ( )
1989Trouillas et al.10ProgressiveIV (450 mg/day) for 20 days 3 weeks + MP6/10 stabilized at 3 years versus 9/10 in plasma exchange regimen versus 0/10 in untreated or azathioprine controls
1991Likosky et al.22ProgressiveIV (400–500 mg) 5 days/week until leukocyte count fell below 4000/mm3No difference versus placebo ( ) at 12, 18, or 24 months
1993Weiner et al.256ProgressiveIV cy/ACTH induction versus modified IV cy/ACTH induction (600 mg/m2 on days 1, 2, 4, 6, 8) followed by 700 mg/m2 IV pulses every 2 months for 2 yearsNo difference between published or modified induction (56% stable at 12 months). Benefit of booster versus no boosters at 24 and 30 months
1998La Mantia et al.30ProgressiveEvery 2 months IV pulses (600 mg/m) for 12 months with or without induction (300 mg/m2 IV for 9 days)At 12 months 75% stable if induction given; 35% stable if no induction
1999Hohol et al.95ProgressiveProgressive induction with 1 g IV MP for 5 days followed by IV pulse cy/MP every 1 month for 1 year, every 6 weeks for 1 year and every 2 months for 1 yearResponse to therapy linked to duration of disease
2003Perini et al.26ProgressiveIV cy/MP 800–1250 mg/m2 monthly for 1 year then every 2 months for 1 yearClinical improvement at 2 years/reduction in Gd+ lesions and T2 lesion volume
2004Zephir et al.111ProgressiveIV cy/MP 700 mg/m2 monthly for 1 yearResponse in patients with clinical attack in the 2 years prior to therapy

Studies of cy in relapsing-remitting and rapidly deteriorating MS
1973Cendrowski23Relapsing remitting and progressive100–300 mg IV for 16–33 days + 50 mg hydrocortisoneNo difference in comparison to patients treated with ACTH or cortisol
1977Gonsette et al.110Relapsing-remittingIV over 2 weeks to achieve leukopenia of 2000 and lymphopenia of 1000. (1–12 g)Stabilization in 62% of patients over 2–4 years. Decrease in relapse rate
1980Gonsette et al.134Relapsing-remittingIV over 2 weeks to achieve leukopenia of 2000 and lymphopenia of 1000. (1–12 g)Stabilization in relapse rate in 76% of patients
1988Killian et al.14Relapsing-remittingMonthly 750 mg/m2 IV pulses for 1 yearA trend showing decreased relapses in 6 treated patients versus 8 placebo patients
1990Millefiorini et al.15Relapsing-progressiveIV cy followed by booster every 2 months for 2 years50% clinically stable at 2 years. No major side effects
1990D’Andrea et al.7Relapsing-remittingIV induction (11 doses 300 mg/m2) then every 6 months for 3 yearsDecrease relapse rate in all patients at 1 year; in the following 2 years, 2 patients worsened, and others were clinically stable
1997Weinstock-Guttman et al.17“Fulminant”IV 500 mg/m + IV MP for 5 days followed by maintenance therapy with cy/methotrexate, MP or IFN-beta-1b13/17 (75%) patients improved or were stable at 12 months; 9/13 (69%) at 24 months
1999Gobbini et al.5Relapsing-remittingMonthly pulses of CTX (1000 mg/m2) given for 12 monthsMRI outcome: decrease in Gd+ lesions following pulse CTX in all patients treated
2000Manova et al.70RelapsesIV MP (200 mg) every other day for 10 doses versus IV cy (200 mg) on alternate days for 10 doses and then monthly for 3 months (total dose: 2.6 g)At 12 months EDSS improved in CTX-treated group versus MP group. No difference between groups at 1 month
2001Khan et al.14Rapidly deteriorating refractory patientsPulse cy 1000 mg/m2 given monthly plus 20 mg IV dexamethasoneClinical improvement or stability in 14/14 patients at 6 months sustained at 18 months following treatment
2001Patti et al.10Rapidly progressive IFN-β nonrespondentsMonthly pulses cy 500–1500 mg/m for 18 monthsReduction in relapses, disability plus T2 MRI burden
2002Smith et al.58Rapidly deteriorating refractory patients3 days IV MP followed by monthly pulses of MP or MP/cy (800 mg/m2) for 6 monthsLess Gd+ lesions at 3 and 6 months in CTX/MP versus MP treated subjects
2004Patti et al.10Clinical and MRI follow-up 36 months after the discontinuation of cy in previous reported patientsMonthly pulses cy 500–1500 mg/m for 18 monthsMaintenance of the results obtained in relapse rate, EDSS, T2 MRI total lesion load and T2 lesions number
2005Reggio et al.30Rapidly progressive IFN-β nonrespondents500–1500 mg/m2 combined with INF-βReduction in relapses plus Gd+ MRI burden
2005de Bittencourt PR1Rapidly progressiveIV cy/MP 3800 mg accidentally givenLong term remission (7 years)
2006Gladstone12Deteriorating and RR and SP MS patients200 mg per kg over 4 daysNo patients increased their baseline EDSS score more than 1.0, improvement in quality of life after 15 months
2008Krishman et al.21MS patients with “active” MRI or relapse or EDSS deterioration in the year before50 mg/kg/die for 4 consecutive daysReduction of EDSS and of the number of Gd+ lesions at end of follow-up (24 months)
2009Patti et al.20Active RR MS patients (>1 relapse in the prior 12 months and >1 Gd+ MRI lesion)Monthly cy, administered to induce a leucopoenia below 1000× mm3, plus methylprednisolone (MP) 1 g for 12 months followed by IFN-β for a further 12 months (cy group); versus IFN-β alone for 2 years (IFN-β group)Reduction of relapse rate and of the number of gadolinium-enhancing lesions at end of follow-up (24 months). Relapse-free patients at the second year were 80% in the cy group versus 40% in the IFN-β group
2009Perumal et al.26Active RR MS patients (at least two relapse in the year before)

Study of cy in pediatric MS
2009Makhani et al.17Children with MS with multiple relapses or EDSS deterioration in the year beforeInduction therapy alone, induction therapy with pulse maintenance therapy or pulse maintenance therapy alone at a dose of 600–1000 mg/m2After 1 year of treatment reduction in relapse rate and a stabilization of disability