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    You are here : Home » MS Research News » Drugs » Novantrone (Mitoxantrone)

    Novantrone (Mitoxantrone)

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    Acute myeloid leukemia in Italian MS patients treated with mitoxantrone

    MitoxantroneSummary: The Italian Mitoxantrone group report data following their evaluation of the incidence and dose-dependency of mitoxantrone (MTX)-associated acute myelocytic leukemia (AML)

    This multicentre study was performed retrospectively and incorporates data from 3,220 patients (63% women) from 40 Italian MS centres. 30 cases of AML in total were identified and as might be expected the mean cumulative dose of MTX was higher in patients with AML. The median interval from the start of therapy to AML diagnosis was longer than expected at 33 months and the rate of mortality associated with AML was 37%.

    The study has identified a higher than expected risk of AML and related mortality in MS patients treated with MTX and the authors recommend that given that AML onset can be quite delayed, exposed MS patients must be monitored for hematologic abnormalities for at least 6 years from the end of therapy.

    To evaluate the incidence and dose-dependency of mitoxantrone (MTX)-associated acute myelocytic leukemia (AML) in the network of Italian multiple sclerosis (MS) clinics.

    We performed a multicenter retrospective cohort study of patients treated with MTX in MS centers under the Italian national health care system between 1998 and 2008. Demographic, disease, treatment, and follow-up information were collected using hospital records.

    Data were available for 3,220 patients (63% women) from 40 Italian centers. Follow-up (mean ± SD) was 49 ± 29 months (range 12-140 months). We observed 30 cases of AML (incidence 0.93% [95% confidence interval 0.60%-1.26%]). The mean cumulative dose was higher in patients with AML (78 vs 65 mg/m(2), p = 0.028). The median interval from the start of therapy to AML diagnosis was longer than expected at 33 months (range 13-84 months); 8 patients (27%) developed AML 4 years or more after the first MTX infusion. The rate of mortality associated with AML was 37%.

    This higher than expected risk of AML and related mortality requires that treatment decisions must be made jointly between clinicians and patients who understand their prognosis, treatment options, and treatment-related risks. The now large exposed MS population must be monitored for hematologic abnormalities for at least 6 years from the end of therapy, to ensure the rapid actions needed for early diagnosis and treatment of AML.

    Authors: Martinelli V, Cocco E, Capra R, Salemi G, Gallo P, Capobianco M, Pesci I, Ghezzi A, Pozzilli C, Lugaresi A, Bellantonio P, Amato MP, Grimaldi LM, Trojano M, Mancardi GL, Bergamaschi R, Gasperini C, Rodegher M, Straffi L, Ponzio M, Comi G; For The Italian Mitoxantrone Group.

    Source: Neurology. 2011 Nov 9. & Pubmed PMID: 22076543 (16/11/11)

    Cardiotoxicity & other adverse events associated with mitoxantrone for MS

    MitoxantroneBackground: Mitoxantrone is used for aggressive multiple sclerosis (MS), but concerns about safety, including cardiotoxicity and other laboratory measures, prevail.

    Objective: To evaluate the incidence and potential predictors of adverse events associated with mitoxantrone at the MS Clinic, University of British Columbia, Canada.

    Methods: Retrospective review of patients treated with mitoxantrone by standard protocol; maximum cumulative dose = 120 mg/m2. Left ventricular ejection fraction (LVEF) was measured with regular multiple-gated acquisition (MUGA) scans; blood cell counts and biochemical liver tests were performed before infusions. Generalized estimating equations were used to examine potential predictors of adverse events (graded according to the Common Toxicity Criteria, version 4) in patients with normal baseline and 1 follow-up MUGA or laboratory assessment.

    Results: All 163 patients (58% women) treated with mitoxantrone from 1999 to 2007 were reviewed. Mean baseline age was 41.9 (SD 10.8) years, cumulative dose was 59.7 (SD 26.0) mg/m2, and median follow-up duration was 14 months (maximum 6.5 years). By study end, 14% developed de novo cardiotoxicity (grade 2) as measured by decreased LVEF, 27% neutropenia (grade 1), 15% anemia (grade 1), and 15% liver toxicity (grade 1). Possible predictors of adverse events included sex, age, disease duration, and cumulative dose; only women exposed to a higher cumulative dose were at a greater risk of anemia (adjusted odds ratio 1.26, 95% confidence interval 1.08–1.48 per 10 mg/m2).

    Conclusions: Based on cardiac and laboratory assessments, mitoxantrone was reasonably well tolerated. However, cardiotoxicity was evident after doses well below current maximum recommended levels. A dose-response effect was not apparent. Findings emphasize the importance of monitoring; the long-term effects of mitoxantrone in multiple sclerosis require investigation.

    E. Kingwell PhD, M. Koch MD, PhD, B. Leung BSc, S. Isserow MD, J. Geddes RN, BSn, P. Rieckmann MD, and H. Tremlett PhD

    From the Faculty of Medicine, Division of Neurology (E.K., M.K., B.L., P.R., H.T.), and Faculty of Medicine, Division of Cardiology (S.I.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Nursing (J.G.), Vancouver Coastal Health, British Columbia, Canada; and Department of Neurology (M.K.), University Medical Center Groningen, University of Groningen; Groningen, The Netherlands.

    Source: Neurology® © 2010 by AAN Enterprises, Inc. (01/06/10)

    Hopes for tailor-made Multiple Sclerosis treatment with Mitoxantrone

    MitoxantroneIn view of the potential severe side effects of new immune therapies for multiple sclerosis (MS), research is now focused on the optimized use of established drugs with known side effect profiles.

    Neurologists in Bochum, working under the auspices of Associate Prof. Andrew Chan (RUB Clinic for Neurology, St. Josef Hospital, Director: Prof. Ralf Gold) are pursuing a pharmacogenetic approach. They were able to prove that the genetic blueprint of specific transporter proteins allows one to draw conclusions on the effectiveness and risk of side effects of the potent agent mitoxantrone. They hope to be able to develop personalized treatment plans for each individual patient.

    The results of this study have been published in BRAIN.

    Mitoxantrone: highly efficient escalation therapy in multiple sclerosis

    According to data supplied by the German Multiple Sclerosis Society’s national MS register (DMSG - Deutsche Multiple Sklerose Gesellschaft), up to 10% of German MS patients have been treated with mitoxantrone in the past few years. Numerous studies have shown that it is highly efficient in suppressing disease activity. It is administered as so-called escalation therapy when other medication no longer suffices and in extremely severe courses of the disease. The high therapeutic efficacy of this substance, which originates from oncology, is coupled with potential, in part dose-dependent side effects on the heart, reproductive organs but also on the bone marrow, thus the pros and cons of its administration must be weighted. Prof. Gold stated that, for this very reason, a lifetime maximum dose of mitoxantrone of 140 mg per m2 body surface may not be exceeded.

    Signs of the involvement of drug carriers in the effectiveness

    Former studies carried out by Dr. Chan and Prof. Gold and their research team had already shown that diverse immune cells respond differently to mitoxantrone. This led to the hypothesis that specific drug carriers – proteins that eliminate mitoxantrone from the cells – have different influences on different cells as well as on the effectiveness of the drug in different patients. The so-called ATP-binding cassette transporters = ABC transporters, thus became the most interesting aspect. The researchers assumed that less potent transporters are accompanied by a higher mitoxantrone concentration within the cells and thus higher effectiveness, and vice versa, that highly functional transporters reduce the effectiveness of the drug.

    Genetic blueprint of the transporter influences the effectiveness 

    They went on to test this hypothesis on a group of MS patients from all over Europe (cooperation with clinics in Dresden, Berg, Göttingen, and Barcelona). It was shown that the differing genetic blueprints of ABC-transporters are indeed linked to the therapeutic response to mitoxantrone. The probability of the patient group with a genetic disposition to low transporter activity responding positively to mitoxantrone is 3,5 times higher than in the group with genetically caused higher transporter activity. Moreover, the functional effects of these genotypes were also confirmed in cell culture experiments and in the MS animal model. Dr. Chan pointed out that the first data gained is also indicative of a correlation between the genetic blueprint of the transporter protein and the side effects of mitoxantrone, for example in isolated cases with cardiac side effects.

    Extensive study in the competence network MS should confirm results

    Dr. Chan explained, “These results furnish hope for personalized mitoxantrone therapy schedules, for example with adapted single doses. This could also result in longer-term total therapy times being possible, a factor which is particularly important because corresponding follow-up therapy periods have not yet been clearly established.” The results of the retrospective study must however first be confirmed in a prospective manner on a large group of patients. The corresponding study within the frameworks of the nation-wide competence network MS, which is subsidized by the Federal Ministry of Education and Research (BMBF – Bundesforschungsministerium), will moreover also investigate further potential pharmacogenetic markers in correlation with mitoxantrone treatment. Prof. Gold and Dr. Chan explained that their primary target is the establishment of a personalized MS treatment strategy for every patient taking the individual aspects of the patient into consideration. These investigations may make it possible to incorporate individual genetic patterns in the decision on the therapy.

    Journal reference:

       1. Cotte S, von Ahsen N, Kruse N, Huber B, Winkelmann A, Zettl UK, Starck M, König N, Tellez N, Dörr J, Paul F, Zipp F, Lühder F, Koepsell H, Pannek H, Montalban X, Gold R, Chan A. ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis. Brain, 2009; 132 (9): 2517 DOI: 10.1093/brain/awp164

    Source: Science Daily © 1995-2009 ScienceDaily LLC (01/09/09)

    Risk of Leukemia with Multiple Sclerosis drug higher than thought


    The risk of developing leukemia as a side effect of a drug for multiple sclerosis (MS) is higher than previously reported, according to a study presented as part of the Late-breaking Science Program at the American Academy of Neurology's 61st Annual Meeting in Seattle, April 25 - May 2, 2009.

    It is an immunosuppressant drug approved by the FDA for treatment of several forms of advancing MS. It is one of only two drugs that has been shown to benefit people with secondary progressive MS who are having attacks. However, the drug can cause heart damage at high total doses. Due to this, the lifetime cumulative dose is equal to about eight to 12 doses over two to three years.

    Previous studies have also shown that the people with MS treated with the drug have an increased risk of developing leukemia. Those studies showed that acute leukemia occurred in .07 percent to .25 percent of MS patients taking mitoxantrone. Today's retrospective study of 2,854 Italian people with MS receiving the drug found that leukemia occurred in .74 percent.

    "This rate is significantly higher than what has been previously reported," said study author Vittorio Martinelli, MD, of University Vita-Salute in Milan, Italy. "The potential risk of leukemia should be carefully considered against the potential benefits of mitoxantrone treatment on every single patient."

    The study participants all had at least one cycle of mitoxantrone treatment and were observed for at least one year. A total of 21 people developed leukemia, eight of whom died. The people who developed leukemia had more treatment cycles than those who did not develop leukemia -- 8.6 cycles versus 7.2 cycles. They also had a greater cumulative dose of mitoxantrone.

    The leukemia occurred an average of three years after the first use of the drug and an average of 18 months after the end of treatment.

    "It is vital that all MS patients treated with mitoxantrone undergo prolonged and careful hematological follow-up to check for acute leukemia," Martinelli said.

    Source: American Academy of Neurology (01/05/09)

    FDA recommendations for cardiac monitoring of patients with multiple sclerosis (MS) who are treated with Novantrone

    FDA Logo

    The FDA has issued an alert informing healthcare professionals about additional recommendations for cardiac monitoring of patients with multiple sclerosis (MS) who are treated with mitoxantrone (marketed as Novantrone and as generics).

    In 2005, the labeling for mitoxantrone was changed to recommend that left ventricular ejection fraction (LVEF) be evaluated before initiating treatment and before administering each dose of mitoxantrone to patients with MS. These changes were established in response to postmarketing and case reports in the medical literature that described decreases in LVEF or frank congestive heart failure in patients with MS who had received cumulative doses of mitoxantrone that were lower than 100 mg/m2.

    Since that time, the FDA has received information from a postmarketing safety study that demonstrated poor adherence to these recommendations in clinical practice. This study used insurance-claims data and medical-record reviews to examine cardiac monitoring patterns in clinical practice. In this study, it was noted that four patients developed congestive heart failure 4 to 17 months after completing therapy with mitoxantrone.

    Given the potential severity of cardiotoxicity and evidence suggesting poor adherence to the recommendations for monitoring cardiac function, the FDA is currently working with the manufacturers of mitoxantrone to remind healthcare professionals of the importance of adhering to the recommendations for patients with MS who are treated with mitoxantrone.

    In addition, the FDA and the manufacturers are now advising that all patients with MS who have finished treatment with mitoxantrone receive yearly quantitative LVEF evaluations to detect late-occurring cardiac toxicity.

    The FDA has issued the following recommendations for patients treated with mitoxantrone.

    For All Patients

    Assess signs and symptoms of cardiac disease with a history, physical examination, and ECG before initiating therapy with mitoxantrone.
    Perform a baseline quantitative evaluation of LVEF.

    For Patients With MS

    Patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone.

    Patients should be assessed for cardiac signs and symptoms with a history, physical examination, and ECG before each dose.

    Patients should undergo a quantitative reevaluation of LVEF before each dose, using the same methodology for each assessment. Additional doses of mitoxantrone should not be administered to patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during mitoxantrone therapy.

    Patients should not receive a cumulative mitoxantrone dose greater than 140 mg/m2.

    Patients should undergo yearly quantitative LVEF evaluations after stopping mitoxantrone to monitor for late-occurring cardiotoxicity, using the same methodology that was used for assessments that were done during treatment.

    Source: FDA (04/08/08)

    Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up

    Mitoxantrone (MTX) is an antineoplastic agent approved for treatment of secondary progressive and rapidly worsening relapsing-remitting multiple sclerosis (MS).

    We designed a longitudinal open-label prospective study to evaluate the efficacy and toxicity of MTX over a 2-year treatment period with a further 3-year follow-up.

    Fifty consecutive MS patients were included and received MTX intravenously (8mg/m2 every 2 months for a total of 12 infusions). Efficacy was assessed clinically and by brain MRI performed before MTX therapy, at the end of treatment and at the end of each year of follow-up.

    Forty-nine patients completed the 5-year study, 44 (89.8%) completed the MTX course, five (10.2%) interrupted the treatment because of side effects. Fifteen (30.6%) patients showed Expanded Disability Status Scale (EDSS) progression on treatment and nine (18.4%) during follow-up. Seventeen (34.7%) patients had enhancing lesions at baseline, nine (18.4%) at the end of treatment, but none at the end of follow-up.

    In conclusion, we observed EDSS progression in about 1/3 of the patients during the treatment period and in 1/5 during the further 3-year follow-up period. This evidence suggests a delayed beneficial effect after MTX treatment is completed with only a minority of patients showing disability progression once the drug was suspended.

    Source: European Journal of Neurology, Volume 14, Number 11, November 2007 , pp. 1281-1287(7) (29/10/07)

    Mitoxantrone treatment in patients with early relapsing-remitting multiple sclerosis
    We investigated the clinical and MRI effects of mitoxantrone (MITOX) administered to 45 patients during the first five years of highly active relapsing-remitting multiple sclerosis.

    Differences occurring between the end of treatment and follow-up (clinical mean: 3.6 years; brain MR: 1.8 years) with respect to baseline variables (EDSS, annualized relapse rate, active T2 lesions, new T1 lesions and number of Gd-enhancing lesions) were analysed using parametric and non-parametric tests.

    One patient developed leukemia four months after the end of the treatment; no other serious adverse events occurred during treatment and the follow-up period.

    A clinically relevant reduction in the annualized relapse rate ( P < 0.0001 at end of treatment and P < 0.0001 at follow-up) and improvement in the EDSS (P < 0.0001 at end of treatment and P = 0.0005 at follow-up) was found. At the end of treatment, 53% of patients experienced no increase in active T2 lesions, while 73% showed no increase in the number of new T1 lesions.

    At follow-up, 41 out of 45 (91%) patients showed a stable MRI pattern and were active-scan free.

    Despite potential serious adverse events, MITOX may be considered an option in selected patients with very active early MS.

    E. Cocco
    Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy

    P. Marchi
    Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy

    C. Sardu
    Department of Public Health, University of Cagliari, Italy

    P. Russo
    Department of Critical Area, University of Florence, Italy

    A. Paolillo
    Department of Critical Area, University of Florence, Italy, Department of Neurological Sciences, University of Rome "La Sapienza", Italy

    MG Mascia
    Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy

    M. Solla
    Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy

    J. Frau
    Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy

    L. Lorefice
    Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy

    S. Massole
    Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy

    G. Floris
    Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy

    MG Marrosu
    Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy

    Source: Multiple Sclerosis 2007; 13: 975—980 (16/10/07)

    Mitoxantrone Can Extend Time to Disease Progression in Worsening Multiple Sclerosis: Presented at AAN
    The results of the Registry to Evaluate Novantrone Effects in Worsening MS (RENEW) study continue to demonstrate the benefits of using immunosuppression with mitoxantrone in patients with multiple sclerosis (MS).

    Researchers presented the study findings here at the American Academy of Neurology (AAN) 59th annual meeting.

    A total of 509 patients receiving mitoxantrone for the treatment of worsening relapsing-remitting MS (WRRMS), progressive-relapsing MS (PRMS) or secondary-progressive MS (SPMS) were enrolled at 46 centres across the United States from April 2001 through January 15, 2007.

    A total of 327 relapses were reported in 241 patients, with the median time to first relapse being 158 days (range, 3 days to 1,215 days), according to lead investigator Victor Rivera, MD, medical director, Maxine Mesinger MS Clinic, Baylor College of Medicine Multiple Sclerosis Centre, Houston, Texas, United States.

    Previous research has shown that early and aggressive treatment with mitoxantrone may delay or limit long-term disability.

    Of the 509 patients enrolled into the RENEW study, 62 continue on mitoxantrone treatment. The majority of reasons given for stopping the study treatment included physician decision (31%) and patient request (27%).

    The authors noted that, in a population representing 736.9 patient years on mitoxantrone, the results of the RENEW study to date continue to support the use of mitoxantrone. Follow-up data continue to be collected for 224 of the 447 patients who stopped treatment, with the intention of extending long-term safety and tolerability data.

    It is well known that the risk of cardiotoxicity with mitoxantrone treatment increases with cumulative doses; the package insert urges that cardiac function be monitored on a regular basis before every dose, the researchers noted.

    This study was supported by EMD Serono.

    [Presentation title: Ongoing Evaluation of the Safety and Tolerability of Mitoxantrone in Worsening Multiple Sclerosis: The RENEW Study. Abstract P06.080]

    Source: Doctor's Guide Copyright (c) 1995-2007 Doctor's Guide Publishing Limited. All rights reserved. (08/05/07)

    Safety and Tolerability of Mitoxantrone for Worsening Multiple Sclerosis Appears Stable in Long Term
    Researchers report that the safety and tolerability of Novantrone (mitoxantrone) in long-term treatment of worsening multiple sclerosis appears to be consistent with its known safety profile.

    The findings were presented at the 22nd Congress of the European Committee for Treatment and research in Multiple Sclerosis (ECTRIMS).

    "In a large sample of patients followed prospectively, we found that the risk/benefit ratio is in keeping with prior knowledge about this drug," said lead investigator Edward Fox, MD, PhD, clinical assistant professor, University of Texas Medical Branch, Austin, Texas.

    Mitoxantrone is currently being evaluated for long-term safety and tolerability in patients with worsening relapsing-remitting multiple sclerosis, progressive relapsing multiple sclerosis and secondary progressive multiple sclerosis in the ongoing, multicenter, open-label Registry to Evaluate Novantrone Effects in Worsening MS (RENEW).

    Dr. Fox reported data on 509 patients in the RENEW trial who initiated Novantrone 12 mg/m2. Patients were excluded from the study if they showed signs of primary progressive MS, history of congestive heart failure, and left ventricular ejection fraction < 50% and if they had received previous treatment with mitoxantrone, other anthracenediones or anthracyclines.

    The investigators evaluated subjects every 3 months during treatment for a total of 3 years and for an additional 2 years for safety evaluation.

    Data were collected from April 2001 to Jan 2006. Mean cumulative dose was 67.5 mg/m2 (8.0-148.6 mg/m2) and mean treatment duration was 1.4 years (0.0-4.0). Sixteen subjects reached the recommended maximum cumulative dose of 140 mg/m2. A total of 355 (70.0%) patients have received concomitant medications for MS.

    Treatment was discontinued by 80% of 508 subjects with validated data. Follow-up data is being collected on 361 subjects regardless of treatment status -- the 104 patients receiving mitoxantrone plus the 257 patients who discontinued mitoxantrone.

    There were 301 relapses during treatment of 221 subjects. Median time to first relapse was 155 days (range: 3-1215).

    Adverse events were reported in 95 patients, who experienced 158 events. The most frequently reported serious adverse events were infectious (34%) and cardiac events (23%). Congestive heart failure occurred in 8 patients, and left ventricular ejection fraction <50% in 4.7% of 340 patients with postbaseline tests.

    Also, 9 of 46 patients with serious infections were severely neutropenic (absolute neutrophil count <500).

    "There have been 7 deaths, 5 unrelated and 2 possibly related to treatment. One therapy-related leukemia case has been reported," the authors wrote in their poster.

    The results, which reflect treatment at higher cumulative mitoxantrone doses (mean: 67.5 mg/m2), appear consistent with the known safety profile, they noted. "Continued patient observation will provide important longer-term safety and tolerability data for mitoxantrone use in clinical practice," they wrote.

    "Since FDA approval in 2000, there is no new safety information except, importantly, that cardiac function should be tested before each dosing," Dr. Fox noted.

    [Presentation title: Ongoing Evaluation of the Safety and Tolerability of Novantrone (Mitoxantrone) Worsening Multiple Sclerosis: The RENEW Study. Abstract P759]

    Source: Doctor's Guide Channels Copyright (c) 1995-2006 Doctor's Guide Publishing Limited. All rights reserved.(03/10/06)

    Very Active Multiple Sclerosis Patients Benefited from COPAXONE(R) Treatment Following Short-Term Induction with Mitoxantrone
    Induction Regime Reduced MRI-Measured Disease Activity by 89% Which Was Sustained Throughout 15-Month Study.

    A new study showed that very active patients who received COPAXONE® (glatiramer acetate injection) therapy alone following short-term induction treatment with mitoxantrone experienced an 89 percent greater reduction (P less than0.0001) compared to those receiving COPAXONE® alone, in Magnetic Resonance Imaging (MRI)-disease activity as measured by Gadolinium (Gd) enhancing lesions of the brain. This initial benefit achieved early on in the study was maintained over the entire 15-month study period. In addition, no adverse events outside of those associated with either treatment when used as monotherapy were observed.

    These data were presented today at the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Madrid, Spain.

    "These new data represent a promising development in the scientific community's effort to identify additional effective treatment strategies for those patients who have particularly aggressive forms of RRMS, many of whom do not respond optimally to traditional disease modifying therapies," said Tim Vollmer, M.D., chairman, Division of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center and the primary investigator in this study. "By putting patients on COPAXONE® after a brief induction period with mitoxantrone, we were able to significantly reduce MRI-disease activity in the brain of active RRMS patients and to sustain this benefit throughout the study."

    About the Study

    This randomised, double-blind study looked at the safety, tolerability and efficacy of COPAXONE® (glatiramer acetate injection) used after short-term induction therapy with mitoxantrone versus COPAXONE® alone. Relapsing-remitting multiple sclerosis (RRMS) patients in this study (n=40) were randomised to receive either COPAXONE® for one year following three months of mitoxantrone (M-GA; n=21), or COPAXONE® alone for 15 months (GA; n=19). The study included patients aged 18-55, who had a Gd-enhancing lesion at the time of an initial screening MRI scan and an EDSS score of <=6.5. Patients entering the study were considered very active with a mean number of Gd-enhancing lesions of 3.75. Subsequent brain MRIs were performed at screening and months six, nine, 12 and 15.

    Results showing a reduction of Gd-enhancing lesions in the M-GA patient cohort compared with the GA cohort were observed as early as six months into the trial (p less than 0.0001) and were maintained throughout the duration of the study (p = 0.0147). The efficacy demonstrated in the GA cohort increased over the entire 15-months trial; a 46 percent reduction in Gd-enhancing lesions was achieved at nine months and at month 15, patients demonstrated a 67 percent reduction compared to entry.

    A relapse was experienced on average eight months prior to baseline in all study participants; after 15 months, the majority of these patients had not experienced a relapse. Patients who received COPAXONE® after mitoxantrone showed a trend in experiencing fewer relapses over the study period. Mean relapse rate during the study period was 0.16 in the M-GA group and 0.32 in the GA group, reflecting a 46 percent greater reduction in relapses in M-GA patients than of those that did not receive mitoxantrone (p=0.31). There was no difference in time to first relapse between the patient cohorts.

    Within study participants, the most frequent adverse events (AEs) associated with the M-GA group were infection, nausea and vomiting, menstruation irregularities and alopecia, and were consistent with known effects of mitoxantrone therapy. Injection site erythema was the most common AE in the GA group.

    "Mitoxantrone carries certain risks which limit its use to a maximum recommended lifetime dose. These difficulties make mitoxantrone an option that is generally reserved for only a small group of patients who have a poor disease prognosis or whose disease does not respond to first-line treatment," said Tim Vollmer, M.D., chairman, Division of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center and the primary investigator in this study. "When used after short-term induction with mitoxantrone, COPAXONE® minimised exposure to mitoxantrone while maintaining treatment effects ongoing, making it a viable treatment option for a broader proportion of the MS population."

    Source: Teva Pharmaceutical Industries Ltd.(29/09/06)

    Long-Term Follow-up Data of Mitoxantrone in Multiple Sclerosis Show Good Safety and Tolerability
    Five-year cardiac and haematological data from a large cohort of multiple sclerosis (MS) patients show that mitoxantrone is generally well tolerated and safe.

    The results on mitoxantrone, which is routinely used in the treatment of leukaemia, malignant melanoma, and breast cancer, were presented here during the 58th annual meeting of the American Association of Neurology (AAN).

    Lead researcher Emmanuelle Le Page, neurologist, Centre hospitalier universitaire de Rennes, Bretagne, France, and colleagues conducted their 5-year follow-up study in 12 centers in France. Mitoxantrone was administered in 307 patients with relapsing-remitting MS, 352 with secondary progressive MS, and 143 with primary progressive MS.

    At 5 years, 776 were assessed clinically at 5 years, for a total of 5361 patient years. The remaining 26 patients were lost to follow-up.

    Mitoxantrone was administered monthly for 6 months in 695, and every 3 months in 107 patients. The mean dose was 78 mg/m2, and 18.5% of mitoxantrone patients received a cumulative dose of more than 100 mg/m2.

    "We observed a decrease in the left ventricular ejection fraction (LVEF) of <50% in 40 patients," Dr. Le Page explained. "One patient suffered congestive heart failure, a 54 year-old woman. Two patients developed acute neoplastic leukemia; the first died, and the second was in stable condition, in hematologic remission, at the time of reporting."

    "Fifty-one patients died on study, 33 of which were MS-related; 17 were deemed not to be mitoxantrone or MS related. One death was mitoxantrone related, the first case of therapy related leukaemia, which occurred 27 months following the initiation of treatment," Dr. Le Page said.

    The researchers also assessed the effects of mitoxantrone on menses in 317 women aged 45 years or less. The data revealed that 27.1% developed intermittent amenorrhea, and 17.3% persistent amenorrhoea.

    The study found a 4.5% risk of amenorrhoea for women who are treated when they are between 25 and 29 years old, a 10% risk in women between 30 and 34 years, and a 21% risk when treated between 35 and 39 years of age.

    "To summarize, when women were treated prior to age 35 years, the risk was 5.4%, and it was 30.7% when they were treated at 35 years of age."

    In the population studied, the risk of developing congestive heart failure at 5 years was 0.5%, the risk for transient symptomatic or persistent asymptomatic LVEF was 3.3% and 1.3%, respectively. The risk for acute neoplastic leukaemia was 0.25%, and according to Dr. Le Page, 0.1% of deaths were related to mitoxantrone.

    Dr. Le Page and colleagues concluded that the mitoxantrone dose of 78 mg/m2 was generally well tolerated as administered in this study.

    "This study pointed out the importance of monitoring cardiac and haematologic tolerance during and after treatment by echocardiography every year, and white blood cell counts every 3 months for 5 years following treatment [with mitoxantrone]," she said.

    [Presentation title: Safety Profile of Mitoxantrone in a French Cohort of 802 Multiple Sclerosis Patients: a 5-Year Follow-Up Study. Abstract S02.006]

    Source: Doctor's guide Channel Copyright (c) 1995-2006 Doctor's Guide Publishing Limited(08/04/06)

    Effects of new treatment are still being investigated

    A multiple sclerosis sufferer is to be given the chance to take a drug that could improve her life.

    Mother-of-six Hazel Monteith was angry when she was offered chemotherapy drug Mitoxantrone earlier this year, only to be told later it was not available.

    While waiting for routine medical checks at the University Hospital of Wales, Cardiff, the Abertridwr mum was shocked to receive a letter saying the treatment was no longer available.

    But after challenging the decision, Mrs Monteith has now been told she CAN have the drug, which could slow down her deterioration from the condition, which affects her mobility. The 37-year-old said: 'It seems to be all systems go. I'm glad as this is what I have been waiting for. We don't know for sure if it will work. But my doctor hopes it will calm down the attacks and give me a better quality of life.'

    She received the good news in a letter from the Cardiff and Vale NHS Trust after contacting her MP Wayne David about the situation.

    It said while the drug's use for MS sufferers was still being investigated, Mrs Monteith would be allowed to take it.

    The drug carries the same possible side effects as chemotherapy, including hair loss and nausea.

    She said: 'I'm willing to be a guinea pig if it means other sufferers can get it in future.'

    Mrs Monteith, who tutors her six children at home with husband Richard, a church minister, is now waiting for her MS consultant to get in touch about starting the medication.

    Source: (23/11/05)

    MS sufferer battles drugs ban
    A father of two has spoken of his fight to get the NHS to prescribe powerful drugs which could prolong his life.

    Ian Williams, who is affected by multiple sclerosis, has been denied a chemotherapy drug called mitoxantrone because Cardiff and Vale NHS Trust does not have enough money to pay for it.

    The Welsh Assembly Government has also said Mr Williams, 33, cannot have the drug because it is only licensed as a treatment for leukaemia in the UK.

    But a number of patients with the progressive form of MS in Wales and the rest of the UK have already been treated with the drug, which can slow down the disease.

    Mr Williams, who has to use a wheelchair to get around, fears that without the treatment he will not live to see his children grow up.

    He said, "The rate I'm going, I will not live to see 40 - and that's being optimistic.

    "MS can be a life-threatening illness, it can be terminal and it's got that much of a hold on me.

    "This treatment will give me more years and that's given me something significant to fight for - extra life."

    Mr Williams, who has two sons, aged 13 and 10 and lives in Pontypool, has suffered a series of debilitating relapses in the last 18 months - the last has left a lesion on his spinal chord, gradually robbing him of his ability to walk.

    His consultant, Trevor Pickersgill at the University Hospital of Wales, in Cardiff, recommended a course of mitoxantrone after Mr Williams had failed to respond to the beta interferon drugs used to treat MS.

    But if he is to benefit from mitoxantrone, he must be prescribed it while he can still walk some distance on his own.

    Mr Williams, who was forced to give up his job as a training officer because of MS, said, "The Welsh Assembly Government's line has been that the reason I can't have this drug is because of the licensing issue.

    "But my medical team believes finances also play a part."

    A spokesman for the MS Society said, "There are a limited number of therapies available at the moment for treating MS and it is our belief that if a neurologist believes a drug can be helpful to a particular patient, he should be able to prescribe it."

    A spokeswoman for Cardiff and Vale NHS Trust said it had a budget of £1.18m to pay for specialist drugs and staff for MS - about £500,000 is allocated to the drugs.

    But because the budget has reached capacity, and funding is allocated on a case-by-case basis, money for a new course of drugs would not be available until an existing patient no longer needed or had finished their treatment.

    She added, "Limited funding is available from Health Commission Wales for high cost drugs and both Health Commission Wales and the trust knew that it would be difficult to meet all our patients' needs this year.

    "We are urgently reviewing the situation and will be making a further statement in the near future."

    An Assembly spokeswoman said, "The provision of therapies to treat patients with multiple sclerosis is a matter for individual clinical judgment based upon the specific needs of the patient.

    "Mitoxantrone is licensed as a chemotherapy treatment for some types of cancer but is not currently licensed for treating patients with MS in the UK. Neurological consultants can prescribe Mitoxantrone off-licence, providing there is trust and local health board agreement on the use of this therapy for MS.

    "A recent Cochrane Review of the use of Mitoxantrone for MS expressed concerns about the long term safety of this drug for MS and concluded that longer follow-up studies were warranted to better explore the efficacy and safety of the drug."

    What is Mitoxantrone?
    Mitoxantrone is primarily used as a chemotherapy drug for patients with leukaemia, but it has been licensed in the US as a means of slowing down the progression of MS.

    While not suitable for all patients with the disease, many have benefited from receiving the powerful drug every three months for a two-year period.

    Despite not being licensed as an MS treatment in the UK, there is a route which allows neurologists to prescribe it to their patients, with their full consent, providing the money is available to pay for it.

    Source: (23/11/05)

    Our NHS won't give me drug to make life better
    A mother of six says the life-enhancing drug she desperately wants has been taken away from her - because of where she lives.

    Affected by Multiple sclerosis,  Hazel Monteith, 37, was offered Mitoxantrone, a chemotherapy drug, to help slow down her deterioration from the condition, which affects her mobility.

    She decided to try it, despite possible side effects like hair loss and sickness.

    But while waiting for routine medical checks at the University Hospital of Wales, Cardiff, the Abertridwr mum was shocked to receive a letter saying the treatment was no longer available.

    She said: 'It is so frustrating. It's the only drug that could help me.

    'Waiting is making me very, very cross. Every day is getting harder.

    'It's available just miles away in Bristol - so why isn't it available to me? No-one is giving me a reason why not.'

    Mrs Monteith says she is housebound for 22 hours out of every 24 and needs a wheelchair to get outside.

    She suffers from debilitating relapses roughly every 10 months and her consultant says they are getting closer together.

    She hoped that Mitoxantrone could make the relapses less frequent, slow down her deterioration and improve her mobility.

    She said: 'Having a relapse feels like my head is full of cotton wool, and someone comes with a fist and pushes and turns it around tight. It's so awful.'

    Each relapse puts her in hospital for up to 10 days and takes six months to recover from, during which time her mobility is affected.

    Husband Richard, 36, a church minister, said: 'They don't have anything else to offer her.

    'It's like hanging a carrot in front of her then taking it away.'

    Mrs Monteith, originally from Northern Ireland, home schools her children, Timothy, 15, Faith, 14, Grace, 12, Laura, 11, and nine-year-old twins Jemma and Janet.

    She said the treatment could mean she spent less time immobilised - and more time with them.

    Mr Monteith said: 'Hazel wants to be with her family as much as possible. She's a mother like any other. To have this chance offered and taken away is depressing.'

    In a bid to get the drug she dearly wants, Hazel Monteith wrote to MP Wayne David, who contacted assembly health minister Dr Brian Gibbons.

    Dr Gibbons, right, replied to the letter to say that Mitoxantrone is not funded by Health Commission Wales as it isn't part of their scheme on treating MS.

    He said: 'I am aware, however, that Cardiff and Vale NHS Trust have chosen to fund several patients with multiple sclerosis to receive Mitroxantrone.

    'This drug is not licensed for use in the treatment of MS and has not been appraised by the National Institute of Clinical Excellence.

    'Therefore, any decision to fund it, is entirely at the discretion of the Trust and not HCW.'

    Dr Gibbons said he wrote to Hugh Ross, the chief executive of Cardiff and Vale NHS Trust, to ask him to look into Mrs Monteith's concerns, and reply to her within 20 days of receiving his request.

    Mrs Monteith is awaiting the reply.

    Cardiff and Vale NHS Trust has said it has reviewed the situation and is prescribing the drug where necessary.

    A spokeswoman said: 'We have urgently reviewed the funding situation for multiple sclerosis drugs and can confirm that our NHS Trust will fund Mitoxantrone for patients when it is the most appropriate treatment.

    'Four drugs are funded by Health Commission Wales for multiple sclerosis and these do not include Mitoxantrone.

    'However, in some circumstances Mitoxantrone is the best treatment for this complex disease and we will prescribe it when necessary.'

    A National Assembly spokeswoman said: 'The provision of therapies to treat patients with MS is a matter for individual clinical judgement based on specific needs of the patient.'Mitoxantrone is licensed as a chemotherapy treatment for some types of cancer but is not currently licensed for treating patients with MS in the UK.

    'Neurological consultants can prescribe Mitoxantrone 'off-license' providing there is Trust and Local Health Board agreement on its use.

    'A recent Cochrane Review of the use of Mitoxantrone for MS expressed concerns about the long-term safety of this drug for MS and concluded that longer follow-up studies were warranted to better explore the efficacy and safety of the drug.'

    Source: South Wales Echo(23/11/05)

    The FDA has added a Boxed Warning

    The FDA has added a "Boxed Warning" to the labeling of Novantrone® (mitoxantrone for injection concentrate). This warning includes additional information about the potential risk of heart damage (cardiotoxicity) and a form of leukemia (secondary acute myelogenous leukemia-AML).

    The new labeling requires repeat testing of cardiac function prior to each dose, in addition to the baseline (i.e., prior to treatment) testing of cardiac function recommended by the original labeling of Novantrone.

    Source: FDA (26/10/05)


    Mitoxantrone Linked to Heart Problems

    Mitoxantrone is the fourth drug approved to treat MS in the US. The Food and Drug Administration approved Mitoxantrone in 2000 to treat MS on the basis of studies conducted only in Europe, not the US.

    What cardiac complications arose during clinical trials?

    The researchers report that several cases of cardiac complications including heart failure have occurred in three mitoxantrone studies. Some of the conditions seen during these studies were:

    • Diminished left ventricular ejection fraction (LVEF), a measure of the heart's blood-pumping strength (more common than congestive heart failure)

    • Congestive heart failure

    The researchers recommend that a test of cardiac function, including LVEF measurement, should be conducted before starting the drug.

    Source: Neurology (24/09/02)

    FDA Approve Novantrone (Mitoxantrone)

    Immunex Corporation announced the approval by the U.S. Food and Drug Administration (FDA) of Novantrone® (mitoxantrone for injection concentrate) as the first therapy approved for secondary progressive Multiple Sclerosis (MS).

    Novantrone is now indicated for reducing neurologic disability and/or the frequency of clinical elapses in patients with secondary progressive, progressive relapsing or worsening relapsing-remitting MS.

    "The approval of Novantrone offers a new treatment option for people with secondary-progressive, progressive-relapsing MS, and worsening relapsing-remitting MS," said Dr. Stephen Reingold, vice president for research at the National Multiple Sclerosis Society.

    Immunex filed for expanded labeling for Novantrone for the treatment of patients with worsening MS on June 7, 1999, and was unanimously recommended for approval on January 28, 2000, by the FDA Peripheral and Central Nervous System Drugs Advisory Panel.

    The new MS indication is based on results from a 24-month Phase III clinical trial in which Novantrone, at a dose of 12 mg/m2, was administered by short IV infusion once every three months. This trial demonstrated that Novantrone had a statistically significant impact on prolonging time to first treated relapse and on delaying disability progression in patients with secondary progressive or progressive relapsing MS. There was also a significant reduction in the mean number of treated relapses. There was a significant reduction in the number of Novantrone patients who had new MS lesions seen on magnetic resonance imaging (MRI).

    "The approval of Novantrone offers new hope for people who otherwise would not have an approved treatment," said Donald Goodkin, M.D., Immunex senior clinical scientist.

    "Novantrone is to me just another word for hope," said Debbie Salazar, Novantrone patient. "I think it's wonderful that it's available."

    The most common side effects of Novantrone in patients with MS in clinical trials have been nausea, hair loss, bladder infections, changes in menstrual cycle, mouth sores, diarrhea, constipation, and changes in cardiac rhythm. Novantrone should not be used by people with serious heart problems, liver disease or certain blood disorders.

    Patients treated with Novantrone may develop serious heart problems. To measure potential changes to the heart, people taking Novantrone should have regular testing of their heart's ability to pump blood. Because of risk of injury to the heart, there is a limit on the total lifetime amount of Novantrone a person can receive.

    For most patients this is approximately eight to 12 doses over two to three years. Patients and their doctors should carefully keep track of how much Novantrone is administered.

    Novantrone can increase potential for infection. Prior to each dose of Novantrone, blood samples should be taken to check blood counts and liver function. Women who are pregnant, trying to become pregnant, or breastfeeding should not use Novantrone. Also, it is recommended that women who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test prior to each dose.

    Novantrone acts in people with MS by suppressing the activity of certain white blood cells known as T cells, B cells and macrophages that are thought to lead the attack on the myelin sheath. It is currently marketed, in combination with corticosteroids, to treat pain in patients with advanced hormone-refractory prostate cancer and for initial therapy of acute nonlymphocytic leukemia.

    Source: Doctor's Guide (13/10/00)

    © Multiple Sclerosis Resource Centre

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