Wise Young
04-16-2002, 07:51 PM
[S23.004] Safety and Efficacy of Combination Therapy with Interferon Beta-1b and Mitoxantrone in Worsening Multiple Sclerosis Using Monthly Gadolinium Enhanced MRI
Douglas R. Jeffery, Neraj B. Chepuri, Jason RosenburgÂ*Winston-Salem, NC
OBJECTIVE: To examine the safety and efficacy of combined therapy with Mitoxantrone (MITX)and Interferon Beta-1b (IFNb-1b)in patients with worsening multiple sclerosis (MS) and a subotimal therapeutic response to IFN-b-1b alone.
BACKGROUND: Despite the demonstrated efficacy of immunotherapeutic agents in the treatment of MS, many patients show a suboptimal response with continued progression of disability and frequent relapse. Mitoxantrone decreases relapse rates, decreases the progression of disability, decreases the accumulation of new T2 and new gadolinium enhancing lesions in both relapsing-remitting (RR)and secondary progressive (SP)MS. The purpose of this trial was to examine the safety and efficacy of combined therapy with IFNb-1b and MITX in patients with worsening MS not controlled on IFNb-1b alone.
DESIGN/METHODS: Ten patients with RR or SP MS were enrolled in the trial. All patients had to be on IFNbb-1b for at least six months, have at least one new enhancing lesion on a screening MRI, one relapse in the six months prior to study enrty, and be neutralizing antibody negative. All patients were required to have normal cardiac function prior to study entry. Monthly MRI scans using triple dose contrast with 30 min delay between contrast administration and scanning were carried out for three months to obtain baseline numbers of new enhancing lesions (NEL). At the end of the baseline phase, MITX was administered at 12 mg/m2 (month 1), and 5 mg/m2 at month 2 and 3. Dosing was then continued at 5 mg/m2 every third month. Monthly MRI scanning was continued for the duration of the study. The primary outcome measure was the number of NELs. Secondary outcome measures included relapse rates, EDSS, and change in T2 and T1 lesion volume.
RESULTS: The addition of MITX to therapy with IFN was well tolerated and there no serious adverse events. Mean white blood cell counts decreased to 2,800 at day 14 but returned to normal levels by day 21. Five upper respiratory tract infections occurred in three patients and one patient had a urinary tract infection. No adverse cardiac events were noted. The mean number of NELs per month in the baseline phase was 2.93±2.46. Mean NELs decreased to 1.09±1.5 following the addition of MITX. Median NEL number decreased 81% following the addition of MITX. New enhancing lesion numbers were suppressed to a greater extent with longer duration of exposure to MITX. At the time of the last scan (month 6)only two patients had new enhancing lesions. Relapse rates decreased 74% following the addition of MITX.
CONCLUSIONS: The combination of therapy with IFNb-1b and MITX was well tolerated and there were no serious adverse events. Both clinical and MRI measures of disease activity responded well to the combination. Relapse rates decreased by 74% and by the time of the last scan only two patients had NELs and volumes were very small. While these results are preliminary, they suggest that patients with aggressive forms of MS failing immunotherapy may benefit from the combined use of IFNb-1b and MITX.
Supported By: This study was supported by grants from Berlex Laboratories and Immunex.
Category - MS and Related Diseases
SubCategory - Therapeutic Trials
Douglas R. Jeffery, Neraj B. Chepuri, Jason RosenburgÂ*Winston-Salem, NC
OBJECTIVE: To examine the safety and efficacy of combined therapy with Mitoxantrone (MITX)and Interferon Beta-1b (IFNb-1b)in patients with worsening multiple sclerosis (MS) and a subotimal therapeutic response to IFN-b-1b alone.
BACKGROUND: Despite the demonstrated efficacy of immunotherapeutic agents in the treatment of MS, many patients show a suboptimal response with continued progression of disability and frequent relapse. Mitoxantrone decreases relapse rates, decreases the progression of disability, decreases the accumulation of new T2 and new gadolinium enhancing lesions in both relapsing-remitting (RR)and secondary progressive (SP)MS. The purpose of this trial was to examine the safety and efficacy of combined therapy with IFNb-1b and MITX in patients with worsening MS not controlled on IFNb-1b alone.
DESIGN/METHODS: Ten patients with RR or SP MS were enrolled in the trial. All patients had to be on IFNbb-1b for at least six months, have at least one new enhancing lesion on a screening MRI, one relapse in the six months prior to study enrty, and be neutralizing antibody negative. All patients were required to have normal cardiac function prior to study entry. Monthly MRI scans using triple dose contrast with 30 min delay between contrast administration and scanning were carried out for three months to obtain baseline numbers of new enhancing lesions (NEL). At the end of the baseline phase, MITX was administered at 12 mg/m2 (month 1), and 5 mg/m2 at month 2 and 3. Dosing was then continued at 5 mg/m2 every third month. Monthly MRI scanning was continued for the duration of the study. The primary outcome measure was the number of NELs. Secondary outcome measures included relapse rates, EDSS, and change in T2 and T1 lesion volume.
RESULTS: The addition of MITX to therapy with IFN was well tolerated and there no serious adverse events. Mean white blood cell counts decreased to 2,800 at day 14 but returned to normal levels by day 21. Five upper respiratory tract infections occurred in three patients and one patient had a urinary tract infection. No adverse cardiac events were noted. The mean number of NELs per month in the baseline phase was 2.93±2.46. Mean NELs decreased to 1.09±1.5 following the addition of MITX. Median NEL number decreased 81% following the addition of MITX. New enhancing lesion numbers were suppressed to a greater extent with longer duration of exposure to MITX. At the time of the last scan (month 6)only two patients had new enhancing lesions. Relapse rates decreased 74% following the addition of MITX.
CONCLUSIONS: The combination of therapy with IFNb-1b and MITX was well tolerated and there were no serious adverse events. Both clinical and MRI measures of disease activity responded well to the combination. Relapse rates decreased by 74% and by the time of the last scan only two patients had NELs and volumes were very small. While these results are preliminary, they suggest that patients with aggressive forms of MS failing immunotherapy may benefit from the combined use of IFNb-1b and MITX.
Supported By: This study was supported by grants from Berlex Laboratories and Immunex.
Category - MS and Related Diseases
SubCategory - Therapeutic Trials