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 (n = 56) or plasma exchange regimen. (n = 57) |
| 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 (n = 21) 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 |