Lights and Shadows of Cyclophosphamide in the Treatment of Multiple Sclerosis
Table 1
Clinical studies of cy in the treatment of MS.
Date
Author
No. of patients
Type of MS
Regimen
Comments and side effects
Study of cy in to treat the relapse of MS
1975
Drachman et al.
6
Acute attacks
4–5 mg/kg IV for 10 successive days
No effect observed on recovery from relapse
Studies of cy in progressive MS
1966
Aimard et al.
1
Progressive
Arrest of disease in progressive MS patients,
1967
Girard et al.
30
Progressive
200 mg/day IV for 4–6 weeks; (4–9 g total)
50% improved or stable at 2 years
1969
Millac and Miller
16
Progressive
Oral, 75–100 mg/day
Toxicity associated with low white blood counts
1975
Hommes et al.
32
Progressive
100 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
1980
Hommes et al.
39
Progressive
400 mg cy + 100 mg prednisone. 8 g total
Stabilization in 69% of patients. Open label, uncontrolled
1981
Theys et al.
21
Progressive
6–8 g given over 3–4 weeks
No effect in patients with moderately advanced MS over 2 years
1983
Hauser et al.
20
Progressive
400–500 mg/day IV for 10–14 days + ACTH
16/20 stabilized at 1 year versus 4/20 with ACTH and 9 out of 18 with plasma exchange regimen
1987
Goodkin et al.
27
Progressive
Inpatient induction for 10–14 days with IV cy/ACTH or outpatient induction with 700 mg/m2 weekly for 6 weeks plus prednisone
Maintenance 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
1987
Myers et al.
14
Progressive
Monthly 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 steroids
3 improved, 9 unchanged, and 2 worsened
1987
Siracusa et al.
14
Progressive
Short course of intensive cy until WBC reached 3000
5 patients discontinued because of side effects. Patients stable, though not improved
1988
Carter et al.
164
Progressive
2-week IV cy/ACTH regimen
81% improved or stable at 1 year. Reprogression in 69% of patients at mean of 17.6 months
1989
Mauch et al.
21
Progressive
8 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
1989
Canadian
55
Progressive
1 g IV on alternate days up to 9 g + oral prednisone
No difference versus placebo () or plasma exchange regimen. ()
1989
Trouillas et al.
10
Progressive
IV (450 mg/day) for 20 days 3 weeks + MP
6/10 stabilized at 3 years versus 9/10 in plasma exchange regimen versus 0/10 in untreated or azathioprine controls
1991
Likosky et al.
22
Progressive
IV (400–500 mg) 5 days/week until leukocyte count fell below 4000/mm3
No difference versus placebo () at 12, 18, or 24 months
1993
Weiner et al.
256
Progressive
IV 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 years
No difference between published or modified induction (56% stable at 12 months). Benefit of booster versus no boosters at 24 and 30 months
1998
La Mantia et al.
30
Progressive
Every 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
1999
Hohol et al.
95
Progressive
Progressive 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 year
Response to therapy linked to duration of disease
2003
Perini et al.
26
Progressive
IV cy/MP 800–1250 mg/m2 monthly for 1 year then every 2 months for 1 year
Clinical improvement at 2 years/reduction in Gd+ lesions and T2 lesion volume
2004
Zephir et al.
111
Progressive
IV cy/MP 700 mg/m2 monthly for 1 year
Response in patients with clinical attack in the 2 years prior to therapy
Studies of cy in relapsing-remitting and rapidly deteriorating MS
1973
Cendrowski
23
Relapsing remitting and progressive
100–300 mg IV for 16–33 days + 50 mg hydrocortisone
No difference in comparison to patients treated with ACTH or cortisol
1977
Gonsette et al.
110
Relapsing-remitting
IV 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
1980
Gonsette et al.
134
Relapsing-remitting
IV over 2 weeks to achieve leukopenia of 2000 and lymphopenia of 1000. (1–12 g)
Stabilization in relapse rate in 76% of patients
1988
Killian et al.
14
Relapsing-remitting
Monthly 750 mg/m2 IV pulses for 1 year
A trend showing decreased relapses in 6 treated patients versus 8 placebo patients
1990
Millefiorini et al.
15
Relapsing-progressive
IV cy followed by booster every 2 months for 2 years
50% clinically stable at 2 years. No major side effects
1990
D’Andrea et al.
7
Relapsing-remitting
IV induction (11 doses 300 mg/m2) then every 6 months for 3 years
Decrease relapse rate in all patients at 1 year; in the following 2 years, 2 patients worsened, and others were clinically stable
1997
Weinstock-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-1b
13/17 (75%) patients improved or were stable at 12 months; 9/13 (69%) at 24 months
1999
Gobbini et al.
5
Relapsing-remitting
Monthly pulses of CTX (1000 mg/m2) given for 12 months
MRI outcome: decrease in Gd+ lesions following pulse CTX in all patients treated
2000
Manova et al.
70
Relapses
IV 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
2001
Khan et al.
14
Rapidly deteriorating refractory patients
Pulse cy 1000 mg/m2 given monthly plus 20 mg IV dexamethasone
Clinical improvement or stability in 14/14 patients at 6 months sustained at 18 months following treatment
2001
Patti et al.
10
Rapidly progressive IFN-β nonrespondents
Monthly pulses cy 500–1500 mg/m for 18 months
Reduction in relapses, disability plus T2 MRI burden
2002
Smith et al.
58
Rapidly deteriorating refractory patients
3 days IV MP followed by monthly pulses of MP or MP/cy (800 mg/m2) for 6 months
Less Gd+ lesions at 3 and 6 months in CTX/MP versus MP treated subjects
2004
Patti et al.
10
Clinical and MRI follow-up 36 months after the discontinuation of cy in previous reported patients
Monthly pulses cy 500–1500 mg/m for 18 months
Maintenance of the results obtained in relapse rate, EDSS, T2 MRI total lesion load and T2 lesions number
2005
Reggio et al.
30
Rapidly progressive IFN-β nonrespondents
500–1500 mg/m2 combined with INF-β
Reduction in relapses plus Gd+ MRI burden
2005
de Bittencourt PR
1
Rapidly progressive
IV cy/MP 3800 mg accidentally given
Long term remission (7 years)
2006
Gladstone
12
Deteriorating and RR and SP MS patients
200 mg per kg over 4 days
No patients increased their baseline EDSS score more than 1.0, improvement in quality of life after 15 months
2008
Krishman et al.
21
MS patients with “active” MRI or relapse or EDSS deterioration in the year before
50 mg/kg/die for 4 consecutive days
Reduction of EDSS and of the number of Gd+ lesions at end of follow-up (24 months)
2009
Patti et al.
20
Active 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
2009
Perumal et al.
26
Active RR MS patients (at least two relapse in the year before)
Study of cy in pediatric MS
2009
Makhani et al.
17
Children with MS with multiple relapses or EDSS deterioration in the year before
Induction therapy alone, induction therapy with pulse maintenance therapy or pulse maintenance therapy alone at a dose of 600–1000 mg/m2
After 1 year of treatment reduction in relapse rate and a stabilization of disability