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MS TREATMENTS: NOVANTRONE (MITOXANTRONE)

 
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PostPosted: Sat Jul 15, 2006 6:27 pm    Post subject: MS TREATMENTS: NOVANTRONE (MITOXANTRONE) Reply with quote

Here's a place to discuss Novantrone if you're on it or thinking about going on it or had it in the past.
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PostPosted: Mon Oct 16, 2006 2:37 pm    Post subject: Reply with quote

From Doctor's Guide, 10/06:

Quote:
Safety and Tolerability of Mitoxantrone for Worsening Multiple Sclerosis Appears Stable in Long Term: Presented at ECTRIMS

By Bruce Sylvester

MADRID, SPAIN -- October 2, 2006 -- 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 here on September 29th 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]


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PostPosted: Mon Nov 13, 2006 3:44 pm    Post subject: (Abstract) Novantrone and immunocompetent cells Reply with quote

From Archives of Neurology:

Quote:
Vol. 63 No. 11, November 2006


Inhibition by Mitoxantrone of In Vitro Migration of Immunocompetent Cells: A Possible Mechanism for Therapeutic Efficacy in the Treatment of Multiple Sclerosis

Tea Kopadze, MD; Thomas Dehmel, PhD; Hans-Peter Hartung, MD; Olaf Stüve, MD, PhD; Bernd C. Kieseier, MD


Arch Neurol. 2006;63:1572-1578.

Background
Damage of the blood-brain barrier and invasion of immunocompetent cells into the central nervous system represent key events in the immunopathogenesis of multiple sclerosis.

Mitoxantrone hydrochloride reduces progression of disability and clinical exacerbations in patients with multiple sclerosis. Its precise mode of action is unclear.

Objective To investigate the effects of mitoxantrone on the migratory capacity of immunocompetent cells ex vivo and in vitro.

Design Case-control study.

Setting Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.

Participants Peripheral blood mononuclear cells (PBMCs) were obtained from 11 patients with multiple sclerosis before and after intravenous mitoxantrone treatment; PBMCs from 5 healthy control donors were treated with mitoxantrone in vitro.

Main Outcome Measures The migratory capacity was studied in an in vitro Boyden chamber assay; cells and their rates of migration were analyzed by light microscopy and flow cytometry. To determine the specificity of our findings, PBMCs were treated with perfosfamide in vitro.

Results Mitoxantrone decreased the migratory capacity of CD14+ monocytes and (to a lesser degree) of CD4+ and CD8+ T lymphocytes. These observations were confirmed when control PBMCs were treated with an equivalent dose of mitoxantrone in vitro. Similar effects were seen when PBMCs were preincubated with perfosfamide. The inhibitory effects of mitoxantrone on the migratory capacity of PBMCs were mediated by reduced matrix metalloproteinase 9 activity, as demonstrated by zymography, polymerase chain reaction, and inhibitory studies.

Conclusion Mitoxantrone may inhibit the migration of inflammatory cells into and within the central nervous system.


Author Affiliations: Department of Neurology, Research Group for Clinical and Experimental Neuroimmunology, Heinrich Heine University, Düsseldorf, Germany (Drs Kopadze, Dehmel, Hartung, Stüve, and Kieseier); and Department of Neurology, University of Texas Southwestern Medical Center at Dallas, and Neurology Section, Medical Service, North Texas Veterans Affairs Health Care System, Dallas (Dr Stüve).




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PostPosted: Wed Jan 03, 2007 8:06 pm    Post subject: (Abstract) Novantrone reduced disability in Iranian MS pts Reply with quote

From PubMed, January 3, 2007:

Quote:
Arch Iran Med. 2007 Jan;10(1):59-64

Mitoxantrone [Novantrone] Reduced Disability in Iranian Patients with Multiple Sclerosis

Hamzehloo A, Etemadifar M.
Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran. ali-hamzehloo@yahoo.com.

BACKGROUND: Multiple sclerosis is a leading cause of disability in young adults. Mitoxantrone has recently been shown to be effective in ameliorating multiple sclerosis activity and reducing the relapse rate. This study aimed to assess the efficacy of mitoxantrone on disease activity and decreasing relapse rate in patients with multiple sclerosis in Iran.

METHODS: This was a clinical trial on patients who received intravenous mitoxantrone, 12 mg/m2 every 3 months. The study was performed at Isfahan Multiple Sclerosis Clinics, affiliated to Isfahan University of Medical Sciences.

This clinical trial was conducted from October 2003 through April 2005.One hundred and forty-seven patients with worsening relapsing-remitting and secondary progressive multiple sclerosis received mitoxantrone, 12 mg/m(2) every 3 months. Clinical assessment was made every 3 months for one year.

RESULTS: Of the 147 patients, 129 (93 females and 36 males) could successfully complete the course of our study. A significant therapeutic effect (P < 0.0001) was detected for the attack rate before and after treatment. The mean attack rate 12 months before treatment was 1.10 (SD = 0.95), which reduced to 0.09 (SD = 0.29) during treatment. The mean expanded disability status scale at the beginning of the treatment was 4.32, which declined to 3.62 (P < 0.0001) after one year.

CONCLUSION: Mitoxantrone was generally well tolerated and reduced progression of disability and clinical exacerbation in our patients. Physicians must be careful about the complications of mitoxantrone especially cardiotoxicity.

PMID: 17198456
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PostPosted: Wed Mar 07, 2007 8:50 pm    Post subject: (Abstract) Novantrone-associated menstrual dysfunction in MS Reply with quote

Scheduled for the upcoming AAN conference in May:

Quote:
Mitoxantrone Therapy-Associated Menstrual Dysfunction in Patients with Multiple Sclerosis

Jessie A. Kerr, Emily Eisenberg, Saud A. Sadiq, New York, NY

OBJECTIVE: To determine the frequency and severity of menstrual irregularities in pre-menopausal women treated with mitoxantrone.

BACKGROUND: Mitoxantrone is an established, FDA-approved treatment for multiple sclerosis. Its long-term use is limited because of the risk of dose-dependent cardiotoxicity and leukemia. However, shorter courses of treatment with mitoxantrone are relatively safe and beneficial in rapidly deteriorating patients.

In pre-menopausal women, there is an additional concern of ovarian failure because of reports of menstrual irregularities associated with chemotherapy. We investigated the incidence of menstrual irregularities in all pre-menopausal women treated with mitoxantrone at our center.

DESIGN/METHODS: Forty-seven consecutively treated pre-menopausal women ranging in age from 18 to 50 who received at least two doses of mitoxantrone (12mg/m2IV infusion every 3 months) were included in the study. A detailed menstrual history was obtained at baseline (pre-treatment), during treatment, and post-treatment, with a follow-up period of one year. Patients taking oral contraceptives were included in the study. Pregnancy was an exclusion criterion. The study was IRB [Institutional Review Board] approved.

RESULTS:
Thirty-six of the 47 patients (77%) reported a change in their menstrual function. Of the 11 patients who had no menstrual dysfunction, 8 were on oral contraceptives and 3 were ages 18, 31, and 37. The frequency of menstrual irregularities correlated with increasing age because below age 35, six of 12 patients (50%) were affected, whereas above age 35, thirty of 35 patients (86%) had menstrual dysfunction. Secondary ovarian failure, characterized by a cessation of menses as well as menopausal symptoms, was seen in only 2 of 23 (9%) patients under 40, but above that age, 13 of 24 (54%) went into menopause. The number of treatment cycles given did not correlate with induced menopause.

CONCLUSIONS/RELEVANCE: Menstrual irregularities occur in the majority of patients receiving mitoxantrone treatment with 32% of women, predominantly over 40, becoming menopausal.

Supported by: Advisory Board of MSRCNY.

Thursday, May 3, 2007 7:00 AM
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PostPosted: Fri Mar 16, 2007 2:22 pm    Post subject: (Abstract) Copaxone alone vs. Copaxone + Novantrone Reply with quote

Scheduled for the upcoming AAN conference in May:

Quote:
[P01.046] Tracking In Vivo Immune Modulation in MS Patients Treated with Glatiramer Acetate (GA) Alone, or with GA Preceded by Mitoxantrone, Provides Novel Insights into the Mode of Action of Therapeutic Strategies That Combine Immune Suppression and Immune Deviation

Amit Bar-Or, Ebrima Gibbs, Masaaki Niino, Tariq Aziz, Sudabeh Alatab, Fu Dong Shi, Denise Campagnolo, Farzaneh Jalili, Susan Rhodes, Tami Yamashita, Boli Fan, Mark Freedman, Ottawa, ON, Canada, Hillel Panitch, Burlington, VT, Douglas Arnold, Montreal, QC, Canada, Timothy Vollmer, Phoenix, AZ, Joel Oger, Vancouver, BC, Canada

OBJECTIVE: To compare the effect of pre-treatment with a brief course of mitoxantrone [Novantrone] followed by GA [Copaxone] therapy, to treatment with GA alone, on the in vivo kinetics of GA-mediated Th2-deviation.

BACKGROUND: In a recent controlled study, GA therapy following a brief course of mitoxantrone (Mitox-GA) was more effective than GA-alone, on clinical and neuroimaging measures, including markers of inflammation (gado+ lesions) and neuroprotection (persistent black holes). Whether these improved outcomes reflect enhanced capacity for GA-mediated Th2-deviation following immune suppression has important ramifications on combination-therapy strategies.

DESIGN/METHODS: GA-induced antibodies (total-IgG; IgG1, IgG2, IgG3, IgG4) were measured serially (ELISA) in serum of n=21 consenting RRMS patients recruited during screening for the above trial. The relationship between IgG1 and IgG4 GA-reactive antibodies is a useful marker of GA-mediated Th2-deviation, as previously reported.

RESULTS: GA-reactive antibodies were undetectable pre-treatment. GA-alone induced strong GA-reactive total-IgG and IgG1-4 responses, peaking at 3 months (p<0.0001 for all), with subsequent partial decreases by 12 months in IgG1-3 (p<0.02 for all), but a significant further IgG4 increase (p=0.007), reflecting the expected GA-mediated in vivo Th2-deviation. GA therapy following mitoxantrone (3 monthly-infusions totaling 36 mg/m2), also induced GA-reactive total IgG, and IgG1-4, peaking at 3 months (p=0.018), although to lower levels than GA-only therapy. By month 12 of GA therapy in the Mitox-GA arm, IgG1-3 tended to decrease (p=0.043; p=0.028; p=0.063, respectively) while IgG4 exhibited an ongoing increasing trend (p=0.064).

CONCLUSIONS/RELEVANCE: The pre-treatment with mitoxantrone appears to partially reduce and/or delay the IgG1 to IgG4 switch characteristic of the Th1 to Th2 switch.

Taken together with the aforementioned neuroimaging observations, our results suggest the enhanced efficacy of Mitox-GA over GA-alone is not due to an enhanced Th2-shift but rather reflects combined anti-inflammatory effects of mitoxantrone and GA, and a preserved neuroprotective effect of GA. These findings will help guide future approaches combining immune-suppression and immune-deviation.


Tuesday, May 1, 2007 7:00 AM [/quote]
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PostPosted: Tue May 01, 2007 3:37 pm    Post subject: (Abstract) Mitoxantrone treatment in early RRMS Reply with quote

From PubMed, May 1, 2007:

Quote:
Mult Scler. 2007 Apr 27

Mitoxantrone treatment in patients with early relapsing-remitting multiple sclerosis

Cocco E, Marchi P, Sardu C, Russo P, Paolillo A, Mascia MG, Solla M, Frau J, Lorefice L, Massole S, Floris G, Marrosu MG.
Centro Sclerosi Multipla, Dipartimento di. Scienze Cardiovascolari e Neurologiche, University of Cagliari, Italy.

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.

PMID: 17468439
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PostPosted: Mon Aug 27, 2007 7:31 pm    Post subject: (Abstract) Mitoxantrone for treating Japanese MS patients Reply with quote

From PubMed, August 23, 2007:

Quote:
Rinsho Shinkeigaku. 2007 Jul;47(7):401-6

[Mitoxantrone for the treatment of Japanese patients with multiple sclerosis]

[Article in Japanese]


Komori M, Tanaka M, Muramoto E, Ohno M, Matsumoto R, Murase N, Kitagawa N, Saida T.
Multiple Sclerosis Center, Utano National Hospital.

We retrospectively evaluated the benefits of mitoxantrone (MITX) treatment in Japanese patients with multiple sclerosis (MS) with more than 3 relapses per year or a deterioration of more than one Expanded Disability Status Scale (EDSS) of Kurtzke score per year despite having IFN beta 1b therapy. Monthly intravenous injections of MITX, 10-12 mg/m2, for 3 months were followed by an additional treatment every 3 months.

Nine patients (6 women, 3 men) with a mean age of 39 years, a mean disease duration of 3.9 years, and a mean EDSS score of 6.7 were studied. Seven patients had long spinal cord lesions (LCL-MS). Most patients tolerated the treatment, although 2 patients stopped MITX therapy after 3 injections because of severe appetite loss. The 7 patients who continued MITX therapy for more than 3 times significantly decreased their relapse rate and EDSS deterioration. The average relapse count in the year preceding initiation of MITX therapy was 4.3 (range: 3-6)/year, EDSS score increased by 2.7 (range: 1-7)/year. The average relapse count was 2.3 (range: 0-4)/year from 0 to 6 months after MITX therapy (p = 0.114), and 1.1 (range: 0-4)/year from 7 to 12 months (p = 0.285). The average EDSS deterioration was -0.4 (range -2-1) from 0 to 6 months after MITX therapy (p = 0.018), and there was no deterioration from 7 to 12 months.

Most patients received granulocyte colony stimulating factor because of leukocytopenia caused by MITX. No patients showed any decrease in cardiac ejection fraction during this observation period. For Japanese MS patients, MITX therapy was very effective in suppressing relapses without incurring severe adverse events.

PMID: 17710882
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PostPosted: Thu Aug 30, 2007 3:05 pm    Post subject: (Abstract) Leukemia due to mitoxantrone Reply with quote

From PubMed, August 30, 2007:

Quote:
Prescrire Int. 2007 Aug;16(90):153-6

Leukaemia due to mitoxantrone

[No authors listed]

(1) Cases of acute leukaemia (usually myeloblastic) have been attributed to mitoxantrone.

(2) A French epidemiological study showed an increased risk of leukaemia in women treated with mitoxantrone for breast cancer, with a relative risk of about 7. The results of studies conducted elsewhere are similar.

(3) The time to onset of leukaemia after mitoxantrone exposure ranges from 8 months to several years. The risk is dose-dependent. The excess risk is particularly high when the cumulative dose is above 13 mg/m2. The prognosis for leukaemia due to mitoxantrone is worse than the prognosis for leukaemia with no known cause.

(4) Cases of leukaemia have also been reported after the use of mitoxantrone to treat other cancers and multiple sclerosis.

(5) This serious adverse effect must be taken into account when choosing a treatment for patients with a relatively long life expectancy. Patients treated with mitoxantrone should be monitored.

PMID: 17724842
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PostPosted: Wed Sep 12, 2007 5:57 pm    Post subject: (Abstract) Mitoxantrone in aggressive RRMS... Reply with quote

From PubMed, September 12, 2007:

Quote:
J Neurol Neurosurg Psychiatry. 2007 Sep 10

Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5-year follow-up observational study of 100 consecutive patients

Emmanuelle LP E, Emmanuelle L E, Grégory T G, Marc C M, Jacques C J, Sean M S P, Gilles E G.
CHU Pontchaillou , RENNES, France.

BACKGROUND:

Mitoxantrone was approved by the French health authority (AFSAPPS) in October 2003 to treat patients with aggressive multiple sclerosis (MS).

OBJECTIVE:

To report long-term effectiveness and safety of Mitoxantrone as induction therapy in aggressive relapsing-remitting MS patients and to assess treatment response factors.

MATERIAL AND METHODS:


100 consecutive aggressive relapsing-remitting MS patients received Mitoxantrone 20 mg monthly combined with methylprednisolone 1g for 6 months. Relapses, EDSS and drug safety were assessed every 6 months up to at least 5 years.

Within 6 months after induction, 73 patients received a maintenance therapy (Mitoxantrone every 3 months: 21; Interferon beta: 25; Azathioprine: 15; Methotrexate: 7; Glatiramer acetate: 5).

RESULTS: During the 12 months following Mitoxantrone start, the Annual Relapse Rate (ARR) was reduced by 91%, 78% of patients remained relapse-free, MRI activity was reduced by 89%, the mean EDSS decreased by 1.2 points (p<10-6) and 64% of patients improved by 1 point EDSS or more. At a longer term, the ARR reduction was sustained (0.29-0.42 up to 5 years), the median time to the first relapse was 2.8 years and disability remained improved up-to 5 years.

Younger age and lower EDSS at Mitoxantrone start were predictive of better treatment response. Three patients presented an asymptomatic decrease of the left ventricular ejection fraction under 50% (1 reversible). One patient was diagnosed with acute myeloid leukemia (remission 5 years after diagnostic).

CONCLUSION:

Mitoxantrone monthly for 6 months as induction therapy followed by a maintenance treatment showed sustained clinical benefit up to 5 years with acceptable adverse events profile in patients with aggressive relapsing-remitting MS.

PMID: 17846110
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PostPosted: Thu Oct 18, 2007 3:12 pm    Post subject: (Abstract) Therapy-related acute nonlymphoblastic leukemia.. Reply with quote

From PubMed, October 18, 2007:

Quote:
J Miss State Med Assoc. 2007 Jul;48(7):206-7

Therapy-related acute nonlymphoblastic leukemia following mitoxantrone therapy in a patient with multiple sclerosis.

Sumrall A, Dreiling B.
Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA. ashleysumrall@bellsouth.net

A 58-year-old male with migraine headaches, complex partial epilepsy, and secondary progressive multiple sclerosis treated with mitoxantrone was admitted to our facility in August 2005 with febrile neutropenia, worsening ataxia, aphasia, cough, and declining mental status. Bone marrow aspirate was consistent with acute nonlymphoblastic leukemia.

Review of the literature reveals ten reported cases of nonlymphoblastic leukemias following treatment with mitoxantrone. Although de novo leukemia cannot be fully excluded, the likelihood of de novo disease is low given the patient's medical history.

This case continues the important discussion of efficacy versus toxicity when selecting mitoxantrone as a therapeutic option for patients with multiple sclerosis. Although leukemia is rarely seen, the potential for this outcome warrants careful consideration before initiating this therapy.

PMID: 17939254


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PostPosted: Sat Oct 27, 2007 6:52 pm    Post subject: (Abstract) Compliance & efficacy of Novantrone... Reply with quote

From the ECTRIMS conference in Prague, Octobeer 11-14, 2007:

Quote:
Compliance and efficacy of mitoxantrone in clinical practice

A. Wundes, G.H. Kraft, J. Bowen, T. Gooley, R. Nash (Seattle, Kirkland, USA)

Background:

Management of worsening multiple sclerosis (MS) continues to pose a major therapeutic challenge. Mitoxantrone has been approved for worsening MS and its efficacy has been demonstrated in trials. Because of side effects, non-compliance and other reasons, the standard protocol of 12 mg/m2 every 3 months for up to 140 mg/m2 is not always followed.

The purpose of this study is to evaluate the results of using mitoxantrone under these conditions.

Objectives:

(1) Examine deviations from the standard protocol. (2) Determine reasons for alterations of mitoxantrone regimen.
(3) Determine under these conditions, if mitoxantrone is therapeutically beneficial.

Methods:

We retrospectively analyzed data from 96 consecutive patients starting mitoxantrone for worsening MS between 9/1999 and 6/2005 in an academic multi-disciplinary MS Center.

Results:

64 patients (67%) did not receive the intended mitoxantrone regimen. Of these, 31 discontinued prematurely due to discouragement or poor tolerability. Fewer patients stopped for safety reasons (asymptomatic LVEF reduction n=7, thrombocytopenia n=1). For the 96 patients studied, the annualized relapse rate (ARR) was 1.07 during the 24 months pre-treatment. It was reduced to 0.54 (p=0.006) during (mean observation time 20 months), and to 0.46 (p<0.001) in the follow-up period (mean 20 months) after discontinuation of mitoxantrone. Seventy-one patients were further stratified based on the number of mitoxantrone infusions (1-3, 4-7, >=8). ARR was reduced in all groups, but only for patients receiving >=8 infusions statistical significance (p=0.001) was reached. Patients were relatively stable with regard to the Expanded Disability Status Scale (EDSS) during mitoxantrone treatment. The mean change of the EDSS was + 0.22 (p= 0.004).

Conclusion:

In the clinical setting, despite frequently incomplete treatment schedules, mitoxantrone stabilizes disease activity in patients with worsening MS. Neurological function in patients was stabilized and relapse rates were reduced. Our data suggest that patients who receive less than full dose still derive some benefit from mitoxantrone. However, for maximum clinical benefit a full dose appears to be needed.


http://tinyurl.com/2nq2nt


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PostPosted: Thu Nov 08, 2007 5:46 pm    Post subject: (Abstract) Chronic myeloid leukemia associated w/Novantrone Reply with quote

From PubMed, November 8, 2007:

Quote:
Mult Scler. 2007 Nov 6

Chronic myeloid leukemia associated with mitoxantrone treatment in a patient with MS

Sadiq S, Rammal M, Sara G.
Division of Hematology/Oncology, Department of Medicine, St. Luke's – Roosevelt Hospital, New York, N.Y.

We report the first case of chronic myeloid leukemia (CML) in a patient with multiple sclerosis (MS) diagnosed within two years of receiving mitoxantrone therapy. Previously only acute forms of leukemia particularly acute promyelocytic leukemia (APL) have been associated with mitoxantrone treatment in MS. This underscores the need for only using mitoxantrone in severe treatment-unresponsive cases of MS.

PMID: 17986509
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PostPosted: Tue Dec 11, 2007 8:09 pm    Post subject: (Abstract) Urachal mucinous adenocarcinoma Reply with quote

From PubMed, December 11, 2007:

Quote:
J BUON. 2007 Oct-Dec;12(4):547-8.

Urachal mucinous adenocarcinoma: a case report

Kountourakis P, Ardavanis A, Mantzaris I, Mitsaka D, Rigatos G.
First Department of Medical Oncology, "Agios Savvas" Anticancer Hospital, Athens, Greece.

Adenocarcinomas account for 0.5-2% of all bladder cancers. Urachal carcinoma is a rare neoplasm which represents 0.01% of all cancers in adults and account for one third of bladder adenocarcinomas.

A 65-year-old white man with an urachal mucinous adenocarcinoma is reported. None of the known predisposing risk factors for bladder cancer -such as tobacco use and professional exposure to chemicals -was identified in his past medical history.

The patient suffered from multiple sclerosis for almost 11 years and in the last 6 years he was treated with low doses of mitoxantrone. He underwent a partial cystectomy and en block excision of the umbilical ligament and remains disease-free after one year.

The development of this rare neoplasm should not be clearly dissociated from multiple sclerosis, either aetiologically sharing an unidentified common causative factor or due to its treatment with mitoxantrone.

PMID: 18067216


urachus = a band of fibrous tissue extending from the bladder to the umbilicus
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PostPosted: Fri Feb 01, 2008 3:59 pm    Post subject: (Article) Mitoxantrone treatment in aggressive MS Reply with quote

From the MS Foundation Internet newsletter, MSFYi, January 2008:

Quote:
MITOXANTRONE TREATMENT IN AGGRESSIVE MS

According to French researchers, mitoxantrone (Novantrone) is effective as induction treatment and for maintenance therapy in those with aggressive relapsing-remitting MS.

The report appeared in the January issue of the Journal of Neurology, Neurosurgery and Psychiatry. "Different MS specialists use different amounts of Novantrone and in different ways," states Daniel Kantor, M.D., Assistant Professor of Neurology and Director of the Comprehensive MS Center at the University of Florida in Jacksonville. "Increasingly, MS specialists are using what is called 'induction therapy.' Rather than simply giving Novantrone every six months as a maintenance therapy, they are trying to 'hit the MS hard' and shut it down for some time. Sometimes, MS attacks our patients hard and we have to fight back with the 'big guns.'"

In the current study, the team continued observation of 100 patients who had begun therapy as early as 1992. They had undergone induction therapy with mitoxantrone 20 mg, along with methylprednisolone 1 g monthly, for six months.

Compared to the 12 months prior to initiation of mitoxantrone, the annual relapse rate was reduced by 91% and 78% of patients remained relapse free during the subsequent 12 months. In all, 64% of patients showed an improvement of at least one point on the Expanded Disability Status Scale (EDSS).

After this induction phase, 73 patients went on to a maintenance phase. Twenty-one did so with mitoxantrone every three months, while the remaining 52 patients received other agents - interferon beta, azathioprine, methotrexate or glatiramer acetate.

The reduction in relapse rate was sustained for up to fice years and disability also remained improved. The median time to the first relapse was 2.8 years. Those who were younger and had a lower EDSS at the start of mitoxantrone treatment showed a better response.

Because this was not a controlled study, the team notes that the data limit straightforward comparison, but the 21 patients who continued with mitoxantrone maintenance therapy showed a lower relapse rate over two years than those who continued with other disease-modifying therapies.

No deaths were related to mitoxantrone and researchers concluded that monthly infusions "for six months as induction therapy followed by maintenance treatment showed sustained clinical benefit for up to five years, with an acceptable adverse events profile."

"Novantrone definitely has its place in MS therapies, but it does have its drawbacks as well," clarifies MSF Medical Advisor Ben Thrower, M.D. "It can affect the heart and lead to congestive heart failure so cardiac tests are required prior to every quarterly infusion to ensure that heart function is not declining from the Novantrone. This potential side effect limits the total lifetime dose of the drug to about two to three years. Leukemia is another potential side effect. We use this treatment primarily in people who present with very aggressive MS, such as frequent relapses, lots of inflammation and poor recovery. Our protocol is to use three monthly doses of mitoxantrone followed by the injectable drug. I have generally been impressed with how this treatment works."
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PostPosted: Sat May 10, 2008 6:22 pm    Post subject: (Abstract) Clinical efficacy for MS patients on Novantrone Reply with quote

Presented at the AAN conference in April 2008:

Quote:
[P02.166] Short and Long-Term Clinical Efficacy and Safety Outcomes for Multiple Sclerosis (MS) Patients Receiving Mitoxantrone Therapy in Western New York Outpatient Clinical Care Settings

Diane Cookfair, David Hojknacki, Robert Zivadinov, Peter Kinkel, Jyotsna Rajeswary, Fredrick Munschauer, Bianca Weinstock-Guttman, Buffalo, NY

OBJECTIVE:

To determine short-term clinical effectiveness and long-term safety of mitoxantrone therapy for MS and identify factors which best predict outcome and rates of/reasons for treatment discontinuation.

BACKGROUND:

Most mitoxantrone outcome studies describe MS patients treated in Europe and/or clinical trials. Use of immunosuppressive/disease modifying therapies, methods of health care delivery, and insurance reimbursement vary by country. This may impact on rates of treatment continuation, efficacy, adverse events and post-treatment monitoring compliance.

DESIGN/METHODS:

129 patients (28 relapsing, 101 secondary progressive(SP); age 18-67) were studied. A priori treatment plans were established for each patient with a goal of stabilization. Cumulative dose median: 33.2 mg/m2 (2.2-80.8). Ninety patients (Group 1) received treatment at a hospital-based MS clinic between 12/01/00 and 07/04/2004; 39 patients (Group 2) in one private practice between 01/01/04 and 01/09/2007.

RESULTS:

Early treatment discontinuation occurred in 55/90 Group 1 patients (61.1%). Reasons for discontinuation: Ineffective, MD decision: 13/55; Patient decision: 20/55; Serious adverse events: 22/55. Likelihood of discontinuation increased with increasing age regardless of EDSS, MS type, dose (p<0.007). One death due to heart failure and one non-Hodgkins lymphoma occurred in Group 1 during post-treatment followup and no therapy-related leukemias in either group. Group 1 patients were followed 2-4 years after treatment; Group 2 followup is ongoing. Patients became less compliant with post-treatment monitoring recommendations over time. Clinically relevant reductions in annualized relapse rate (ARR) were observed (mean baseline ARR=0.91; 12month ARR=0.38; p<0.001). Patients with >=1 relapse/year pre-study experienced a 74.0% reduction from baseline. 34 Group 1 SP patients had worsened by >=1.0 EDSS point during the 12 months before starting mitoxantrone; 88.2% stabilized (N=28) or improved by>=1 EDSS points (N=2) 12 months after starting mitoxantrone.

CONCLUSIONS/RELEVANCE:

Mitoxantrone safety and efficacy results were consistent with known profiles, with significant clinical benefit observed during year one. Increased emphasis on post-treatment monitoring among MS patients receiving mitoxantrone in outpatient care settings is recommended.

Supported by: EMD Serono, Inc.
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PostPosted: Wed Jul 30, 2008 7:18 am    Post subject: FDA Novantrone warning Reply with quote

The US FDA has issued a new Novantrone warning, requiring annual checks:

Quote:
2008 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements

Mitoxantrone Hydrochloride (marketed as Novantrone and generics)

Audience: Neurological and Oncological healthcare professionals, risk managers

[Posted 07/29/2008] FDA reminded health care professionals who treat patients with mitoxantrone about recommendations that left ventricular ejection fraction (LVEF) be evaluated before initiating treatment and prior to administering each dose of mitoxantrone. FDA offered additional recommendations for cardiac monitoring to detect late-occurring cardiac toxicity, and provided information for patients with multiple sclerosis who receive the drug.

These recommendations were established in 2005 in response to post-marketing reports 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, FDA has received information from a post-marketing safety study that demonstrated there is poor adherence to these recommendations in clinical practice. FDA is working with the manufacturers to educate healthcare providers to adhere to cardiac monitoring recommendations for patients with MS.

[July 29, 2008 - Information for Healthcare Professionals - FDA]



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PostPosted: Fri Aug 01, 2008 1:54 pm    Post subject: More on the Novantrone warning Reply with quote

From Medscape Today, July 30, 2008:

Quote:
Additional Cardiac Monitoring for Patients on Mitoxantrone

Sue Hughes





July 30, 2008 — 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) [1].

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.

For patients With cancer

~The possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin should be considered when weighing the benefits and risks of mitoxantrone.
~The presence or history of cardiovascular disease, previous or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or the concomitant use of other cardiotoxic drugs might increase the risk of cardiac toxicity. LVEF should be monitored regularly after the initiation of therapy in patients with these risk factors.

[1]Information for healthcare professionals: mitoxantrone hydrochloride (marketed as Novantrone and generics). FDA Alert. July 29, 2008. Available at http://www.fda.gov.

The complete contents of Heartwire, a professional news service of WebMD, can be found at http://www.theheart.org, a Web site for cardiovascular healthcare professionals.

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PostPosted: Sat Aug 16, 2008 10:41 am    Post subject: (Abstract) Mitoxantrone-induced amenorrhea in MS... Reply with quote

From PubMed, August 15, 2008:

Quote:
Mult Scler. 2008 Aug 13

Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the FEMIMS study

Cocco E, Sardu C, Gallo P, Capra R, Amato MP, Trojano M, Uccelli A, Marrosu MG; the FEMIMS group.
Department of Cardiovascular and Neurological Science, Multiple Sclerosis Centre, University of Cagliari, Cagliari, Italy.

Background

Improved prognosis in women with multiple sclerosis (MS) undergoing immunosuppressive treatment with mitoxantrone (MITO) has led to an increased interest in the effect of such treatments on fertility.

FErtility and Mitoxantrone In MS (FEMIMS) is a collaborative retrospective study aimed at evaluating the impact of MITO treatment on fertility in women with MS.

Methods

Occurrence of chemotherapy-induced amenorrhea (CIA) was evaluated in 189 women with MS treated with MITO before the age of 45. An "ad hoc" questionnaire, paying particular attention to onset of CIA either during or post-MITO treatment, was administered to each patient. The probability of CIA was calculated using a multivariate logistic regression analysis taking into account age at exposure, cumulative dose, and use of estroprogestinic (EP) drugs during treatment.

Results

Forty-eight (26%) patients presented CIA following MITO. The probability of CIA was increased by 2%/mg/m(2) of cumulative dose and by 18% for each year of age, whereas it was reduced by administration of EP during treatment.

Conclusions

MITO treatment may affect reproductive capacity in women with MS. Patients of childbearing age should be properly counseled before MITO treatment and EP therapy should be administered to reduce the risk of CIA.

PMID: 18701568
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PostPosted: Sun Mar 01, 2009 2:50 pm    Post subject: (Abstract) Therapy-related acute leukemia.. Reply with quote

From Multiple Sclerosis, February 27, 2009:

Quote:



First published on February 27, 2009
Multiple Sclerosis 2009, doi:10.1177/1352458508100967


Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it?

R Ellis* and M Boggild
Walton Centre for Neurology and Neurosurgery, Neurological Sciences, Liverpool, UK

Therapy-related acute leukaemia (TRAL) is a concern for neurologists and patients when considering treatment with Mitoxantrone for multiple sclerosis (MS). The timing of this complication, risk, mortality and relationship to exposure remain uncertain.

Methods

We searched literature for publications relating to Mitoxantrone in MS, reviewed publication references and handsearched abstract lists to identify case-series reporting follow-up and complications of treatment with Mitoxantrone. We combined this with our local database of 250 cases treated since 1997. We also identified all reported individual cases of TRAL and extracted data reporting exposure (dose or mg/m2), timing and outcome of TRAL.

Results

Case-series including 5472 patients were identified; mean dose of Mitoxantrone was 74.2 mg/m2 (range:12–120 mg/m2). TRAL was diagnosed in 0.30% (1 in 333). In 34 TRAL cases, sufficient data was available to inform analysis of exposure. Onset was a median of 18.5 months following Mitoxantrone treatment (range:4–60). Acute Myelocytic Leukaemia and Acute Promyelocytic Leukaemia represented 46.4% each of the leukaemia subtypes. Six of 25 TRAL patients, where outcome was reported, died (24%). Over 80% of cases occurred in patients exposed to >60 mg/m2, with a relative risk of 1.44 (CI95%:1.18–1.70) when comparing total dose >60 mg/m2 against <60 mg/m2 strongly suggesting a relationship between risk of TRAL and total dose.

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PostPosted: Thu Apr 30, 2009 2:32 pm    Post subject: Leukemia risk greater w/Novantrone than previously thought Reply with quote

Presented at the AAN conference in Seattle this week and summarized in MSFYi, the MS Foundation Internet newsletter, April 30, 2009:


Quote:
A retrospective study of 2,854 Italian people who took mitoxantrone treatments for MS found that .74 percent developed leukemia, which is roughly triple the number recorded in previous studies.

Mitoxantrone is an immunosuppressant drug approved by the Food and Drug Administration (FDA) for treatment of several forms of advancing MS. It is normally used in very active relapsing-remitting or secondary progressive MS, where relapses are still a significant feature.

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 mitoxantrone and an average of 18 months after the treatment ended.

The study’s author, Vittorio Martinelli, M.D., of University Vita-Salute in Milan , Italy , recommends that anyone treated with mitoxantrone should undergo a prolonged and careful hematological follow-up to check for acute leukemia.
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PostPosted: Fri Jun 12, 2009 8:39 pm    Post subject: (Abstract) Reply with quote

Interesting that the interferons are the only MS drug approved for use in Japan at present.

From PubMed, June 12, 2009:

Quote:
Brain Nerve. 2009 May;61(5):575-80.

[Mitoxantrone for the treatment of patients with multiple sclerosis]

[Article in Japanese]


Komori M, Kondo T, Tanaka M.
Department of Neurology, Graduate School of Medicine, Kyoto University, Kawaramachi 54, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

Mitoxantrone was originally developed as an antineoplastic agent. However, it is currently used as an immunosuppressant in the treatment of multiple sclerosis (MS).

A series of European studies over a 10-year period have revealed the clinical benefits and tolerability of mitoxantrone. On the basis of the favorable findings reported by the above-mentioned studies, the FDA approved the use of mitoxantrone for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary progressive MS, progressive relapsing MS, or worsening relapsing-remitting MS but not for treating patients with primary progressive MS.

The therapeutic modalities available in Japan are very limited. Interferon beta (IFN-beta), which is an immunomodulatory drug, is the only drug approved in Japan for treating MS; however, it is only partially effective or rather ineffective for treating patients with rapidly worsening or fulminant MS.

Our pilot studies confirmed the benefits of mitoxantrone in Japanese patients with MS, and in this study, we review its potential appliciation for the treatment of MS by Japanese neurologists.

PMID: 19514518


The abstract can be seen here.
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PostPosted: Tue Sep 08, 2009 7:37 am    Post subject: (Article) Hopes for tailor-made MS treatment w/Novantrone Reply with quote

From Science Daily, September 1, 2009:

Quote:
Hopes For Tailor-made Multiple Sclerosis Treatment With Mitoxantrone

In 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

Adapted from materials provided by Ruhr-Universitaet-Bochum, via AlphaGalileo
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PostPosted: Sat Feb 06, 2010 7:33 pm    Post subject: (Abstract) Mechanisms of action of Novantrone... Reply with quote

From PubMed, February 6, 2010:

Quote:
Neurology. 2010 Jan 5;74 Suppl 1:S41-6.

Mitoxantrone and cytotoxic drugs' mechanisms of action

Vollmer T, Stewart T, Baxter N.

Department of Neurology, University of Colorado Denver, Aurora, CO 80045, USA. Timothy.Vollmer@UCD.edu

Evidence has suggested that early, aggressive intervention may improve both short- and long-term outcomes in patients with multiple sclerosis (MS). Cytotoxic agents may offer advantages in this setting, particularly when used as an induction or add-on therapy with immunomodulators.

Immunosuppression is the mechanism of action common to all cytotoxic drugs; individual subtleties in immunoregulatory actions are likely of minor importance. In the United States, mitoxantrone is currently the only cytotoxic agent approved for the treatment of MS (secondary-progressive, progressive-relapsing, and worsening relapsing-remitting forms).

Therapies in phase III development include cyclophosphamide, mycophenolate mofetil, cladribine, and teriflunomide. All these drugs have exhibited efficacy in controlled clinical trials, although the degree of benefit with respect to MRI and clinical endpoints has varied both within and among the various agents.

Further investigations are needed to determine whether cytotoxic drugs represent a substantial improvement over treatments that have a more targeted impact on the immune system.

PMID: 20038762


The abstract can be seen here.
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PostPosted: Thu Apr 22, 2010 6:12 pm    Post subject: (Abstract) Acute leukemia in MS patients on Novantrone... Reply with quote

Presented at the AAN conference in Toronto, April 10-17, 2010:

Quote:
Acute Leukemia in Multiple Sclerosis Patients Treated with Mitoxantrone in the Postmarketing Setting: The EMD Serono Experience

Ahmad Al-Sabbagh, Daryl Dawson, Randy Bennett, Fernando Dangond, Rockland, MA

OBJECTIVE:

To characterize the postmarketing reports of acute leukemia secondary to Novantrone (mitoxantrone for injection concentrate) therapy of US patients with multiple sclerosis (MS).

BACKGROUND:

The postmarketing incidence of leukemia in Novantrone-treated MS patients, as noted in the package insert for Novantrone (2009), has been estimated at approximately 0.25% (2/802) and 0.60% (3/509) from 2 different cohorts.

DESIGN/METHODS:

Data were compiled from physician reports of acute leukemia secondary to mitoxantrone therapy for MS. All cases were submitted to EMD, Serono, Inc. between March, 2003 and April, 2009, including 3 cases from the Registry to Evaluate Novantrone in Worsening MS (RENEW) study.

RESULTS:

Through April, 2009, 44 cases of secondary acute leukemia in mitoxantrone-treated MS patients had been reported; not all patient characteristics were available in each case. Median age of the patients was 49 (range, 2968; n=41), and 70% (31/44) were women. Mean (SD, range) cumulative dose of mitoxantrone was 84.9 mg/m2 (23.1, 48135; n=20), and the median (range) latency of leukemia onset after the end of mitoxantrone therapy was 17 (060; n=32) months. The most common types of leukemia reported in this population were acute myelogenous leukemia (n=17, 38.6%) and its subtype acute promyelocytic leukemia (n=16, 36.4%). Other types of leukemia reported included leukemia and secondary leukemia not otherwise specified (NOS) (n=7, 15.9%), chronic myeloid leukemia (n=2; 4.5%), and 1 case each (2.3%) of pre-B cell acute lymphoblastic leukemia, and myelodysplasia.

CONCLUSIONS/RELEVANCE:

Leukemia secondary to mitoxantrone therapy may be a significant risk factor for patients with MS. Although a definitive estimate of the risk may be difficult and no clear dosedependence was observed, the possibility of this adverse event warrants ongoing investigation and monitoring of patients receiving mitoxantrone for MS.

Supported by: Sponsored by EMD Serono, Inc.
Category - MS and Related Diseases - Clinical Science

Tuesday, April 13, 2010 7:30 AM

Poster Session I: Multiple Sclerosis and Related Diseases: Clinical Research/Epidemiology (7:30 AM-12:00 PM)



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PostPosted: Sat May 01, 2010 6:35 pm    Post subject: (Abstr.) Cardiotoxicity & other adverse events ... Reply with quote

From PubMed, April 30, 2010:

Quote:
Neurology. 2010 Apr 28.

Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS

Kingwell E, Koch M, Leung B, Isserow S, Geddes J, Rieckmann P, Tremlett H.

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.


BACKGROUND:

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/m(2). 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/m(2), 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/m(2)).

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.

PMID: 20427751


The abstract can be seen here.
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PostPosted: Thu May 06, 2010 5:06 pm    Post subject: (Abstract) Evidence report on efficacy, safety... Reply with quote

From PubMed, May 5, 2010:

Quote:
Neurology. 2010 May 4;74(18):1463-70.

Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Marriott JJ, Miyasaki JM, Gronseth G, O'Connor PW.

The Multiple Sclerosis Clinic, St. Michael's Hospital, Division of Neurology, University of Toronto, Canada.

Comment in:

Neurology. 2010 May 4;74(18):1410-1.


OBJECTIVE:

The chemotherapeutic agent mitoxantrone was approved for use in multiple sclerosis (MS) in 2000. After a review of all the available evidence, the original report of the Therapeutics and Technology Assessment Subcommittee in 2003 concluded that mitoxantrone probably reduced clinical attack rates, MRI activity, and disease progression. Subsequent reports of decreased systolic function, heart failure, and leukemia prompted the US Food and Drug Administration to institute a "black box" warning in 2005. This review was undertaken to examine the available literature on the efficacy and safety of mitoxantrone use in patients with MS since the initial report.

METHODS:

Relevant articles were obtained through a review of the medical literature and the strength of the available evidence was graded according to the American Academy of Neurology evidence classification scheme.

RESULTS:

The accumulated Class III and IV evidence suggests an increased incidence of systolic dysfunction and therapy-related acute leukemia (TRAL) with mitoxantrone therapy. Systolic dysfunction occurs in approximately 12% of patients with MS treated with mitoxantrone, congestive heart failure occurs in approximately 0.4%, and leukemia occurs in approximately 0.8%. The number needed to harm is 8 for systolic dysfunction and 123 for TRAL. There is no new efficacy evidence that would change the recommendation from the previous report.

CONCLUSIONS:

The risk of systolic dysfunction and leukemia in patients treated with mitoxantrone is higher than suggested at the time of the previous report, although comprehensive postmarketing surveillance data are lacking.

PMID: 20439849


The abstract can be seen here.

The entire article can be seen here.
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PostPosted: Tue Aug 24, 2010 8:56 am    Post subject: (Abstract) Novantrone for worsening MS... Reply with quote

From PubMed, August 24, 2010:

Quote:
Clin Neurol Neurosurg. 2010 Aug 18.

Mitoxantrone for worsening multiple sclerosis: Tolerability, toxicity, adherence and efficacy in the clinical setting

Wundes A, Kraft GH, Bowen JD, Gooley TA, Nash RA.

University of Washington, School of Medicine, Seattle, WA, USA.

BACKGROUND:


The treatment of worsening multiple sclerosis (MS) remains challenging. Mitoxantrone, an anthracyclines, is approved as a treatment for worsening MS. However, systematic analyses of its tolerability and effectiveness outside of controlled trials are few. Certain advantages, including easy application and simple monitoring, need to be balanced against its toxicity.

OBJECTIVE:

To study efficacy, tolerability and feasibility of mitoxantrone treatment in a regular clinical setting.

METHODS:

Retrospective analysis of data from 96 MS patients with worsening MS before, during, and after mitoxantrone. Specifically, we addressed adherence and reasons for deviations from the intended treatment schedule regarding tolerability and safety, and consequences of deviations on clinical efficacy.

RESULTS:


Schedule deviations were frequent. Only a third of patients received the intended cumulative dose. Hematological toxicity was generally mild and transient. In 7 patients, treatment was withheld because of impact on ventricular ejection fraction, in the absence of clinical symptoms of cardiac failure. No malignancies were observed. With respect to clinical benefit, most patients remained stable and the relapse rate decreased with mitoxantrone initiation in both relapsing and secondary MS patients (p<0.0001). A possible modest non-significant dose-effect on annualized relapse rates was observed.

CONCLUSION:

Mitoxantrone may be considered for treatment of refractory MS. Poor tolerability impacted adherence but dose-limiting safety events were rare. Mitoxantrone needs to be carefully assessed in light of recent data on risk of cardiotoxicity and leukemia.

PMID: 20727669


The abstract can be seen here.
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PostPosted: Tue Sep 28, 2010 5:49 pm    Post subject: Novantrone: Update on cardiac risk Reply with quote

An abstract of this study is in the May 1 post in this thread. From Journal Watch Neurology, September 28, 2010:

Quote:
Summary and Comment

Mitoxantrone: Update on Cardiac Risk

In a retrospective chart review, posttreatment cardiotoxicity occurred more frequently than was observed in clinical trials.

In 2000, mitoxantrone was approved by the FDA for secondary progressive, worsening relapsing-remitting, and progressive-relapsing forms of multiple sclerosis (MS). The drug's use has been limited by concerns about potential cardiotoxicity and acute leukemia. To provide more data on its cardiotoxicity, researchers conducted this retrospective chart review of 163 patients followed at their clinic for nearly 10 years.

Median follow-up duration was slightly more than 1 year, and mean cumulative dose (59.7 mg/m2) was well below the suggested lifetime ceiling of 140 mg/m2. Nonetheless, 14% of mitoxantrone-treated patients with normal baseline left ventricular ejection fractions experienced decreased ejection fractions on follow-up multiple-gated acquisition (MUGA) scans. This effect persisted in half of these patients and reversed in three patients (17%); the other six patients did not receive a follow-up MUGA study. One patient developed congestive heart failure. Sex, age, disease duration, and cumulative dose were not predictors of cardiac risk. The authors also identified other adverse effects of mitoxantrone (neutropenia, liver toxicity, and anemia).

Comment:

Recently, the FDA imposed stringent guidelines for mitoxantrone use, requiring that treated patients undergo annual echocardiograms indefinitely to detect late-developing cardiac damage. Although this study showed no relation between total dose and cardiac effect, other studies involving higher mean dosages have done so. The lack of association in this study likely reflects the restricted dosing range. The cardiotoxicity reported here is greater than was seen in the phase II and III trials and in some but not all postmarketing studies. This difference is especially noteworthy considering the low cumulative doses and short follow-up. Taken together with other postmarketing work, including some studies suggesting a risk for leukemia as high as 3% with mitoxantrone (Neurology 2010; 74:1463), these finding clearly indicate that clinicians must carefully consider safety risks before prescribing mitoxantrone.

— James Stankiewicz, MD

Dr. Stankiewicz is Director of Clinical Education, Partners MS Center, and Instructor in Neurology, Harvard Medical School, Boston.

Citation(s):

Kingwell E et al. Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS. Neurology 2010 Jun 1; 74:1822.

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PostPosted: Fri Oct 05, 2012 5:27 pm    Post subject: (Abst.) Long-term treatment risks in MS... Reply with quote

From Multiple Sclerosis Journal, October 4, 2012:

Quote:
Long-term treatment risks in multiple sclerosis: risk knowledge and risk perception in a large cohort of mitoxantrone-treated patients

A Hofmann1
JP Stellmann1
J Kasper1,2,3
F Ufer1
WG Elias4
I Pauly5
J Repenthin6
T Rosenkranz7
T Weber8
S Köpke1,9
C Heesen1
on behalf of the MS Network Hamburg

1Institute for Neuroimmunology and Clinical MS Research (INIMS) and Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany

2Department of Primary Medical Care, University Medical Center Hamburg, Germany

3Unit of Health Science and Education, University of Hamburg, Germany

4Private Practice, Germany

5Department of Neurology, Asklepios Klinik Nord, Germany

6Department of Neurology, Asklepios Klinik Barmbek, Germany

7Department of Neurology, Asklepios Klinik St. Georg, Germany

8Department of Neurology, Marienkrankenhaus, Germany

9Nursing Research Group, Institute for Social Medicine, University of Lübeck, Germany

Jan-Patrick Stellmann, Institute for Neuroimmunology and Clinical MS-Research and Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Email: j.stellmann@uke.uni-hamburg.de
AH and JPS contributed equally to this manuscript.

Background:

Balancing treatment benefits and risks is part of a shared decision-making process before initiating any treatment in multiple sclerosis (MS). Patients understand, appreciate and profit from evidence-based patient information (EBPI). While these processes are well known, long-term risk awareness and risk processing of patients has not been studied. Mitoxantrone treatment in MS is associated with long-term major potential harms – leukaemia (LK) and cardiotoxicity (CT). The risk knowledge and perception among patients currently or previously treated with mitoxantrone is unknown.

Objectives:

The objective of this article is to conduct a retrospective cohort study in greater Hamburg, Germany, to estimate risk awareness and perception in MS patients treated with mitoxantrone.

Methods:

MS patients with at least one dose of mitoxantrone between 1991 and 2010 from six major MS centres in greater Hamburg received a questionnaire assessing risk awareness and perception as well as a written EBPI about mitoxantrone-associated LK and CT.

Results:

Fifty-one per cent in the cohort of n = 575 patients returned the questionnaire. Forty per cent correctly estimated the risk of LK (CT 16%); 56% underestimated the risk (CT 82%). Reading the information increased the accuracy of LK risk estimation, and patients did not report an increase of worries. The EBPI was appreciated and recommended by 85%.

Conclusion:

Risk awareness of mitoxantrone-treated patients is insufficient, but can be increased by EBPI without increasing worries. Continued patient information during and after treatment should be implemented in management algorithms.



The abstract can be seen here.
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PostPosted: Sat Apr 20, 2013 3:41 pm    Post subject: (Abst.) Novantrone-related acute leukemia in MS... Reply with quote

From PubMed via the NTK Institute's Today in General Medicine, April 19, 2013:

Quote:
Neurology. 2013 Apr 16;80(16):1529-33.

Mitoxantrone-related acute leukemia in MS: An open or closed book?

Chan A, Lo-Coco F.

From the Department of Neurology (A.C.), St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany; and the Department of Biomedicine and Prevention (F.L.-C.), University of Tor Vergata & Fondazione Santa Lucia, Rome, Italy.

Despite the long-standing and extensive use of mitoxantrone (MTZ) for the treatment of aggressive forms of multiple sclerosis (MS), especially in Europe, its benefit-risk profile remains controversial. In particular, the risk of developing therapy-related acute leukemia (TRAL) and cardiotoxicity have led to treatment restrictions for MTZ; however, the precise risk for these severe complications is still unclear.

Here we review current data on TRAL incidence, research strategies aimed at individual risk stratification, and provide recommendations for hematologic monitoring. A recent meta-analysis indicates a TRAL risk of approximately 0.81%, more than 10-fold higher than in previously reported meta-analyses (0.07%).

There also appear to be considerable differences among countries, with recent TRAL risk estimates from Italy as high as 0.93%, compared to the 0.25%-0.41% risk reported from Germany and France. Whereas methodologic differences may partly account for some of these differences, high regional variability may point to exogenous factors such as heterogeneous treatment protocols and cotreatments.

In addition, genetic risk factors (MTZ metabolism, DNA repair) might contribute to the individual risk profile.

The case of potentially curable MTZ-induced secondary leukemia highlights the need for close hematologic monitoring during and after therapy. Intensive collaboration between neurologists and hematologists will likely provide benefits both for research efforts aimed at unraveling TRAL pathogenesis and for clinical practice with improved identification and monitoring of patients at higher risk of MTZ-induced TRAL. This is of particular importance, since treatment alternatives, especially in secondary progressive MS, are sparse.

PMID:23589639
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