January 24, 2003
Research Programs Department
An international team of investigators led by Hans-Peter Hartung, MD (Heinrich Heine University, Düsseldorf, Germany) has published results of the largest clinical trial of mitoxantrone (Novantrone®) in persons with multiple sclerosis. The results of this and a previous trial led to the drug’s approval in 2000 by the U.S. Food and Drug Administration for worsening forms of MS. The study appeared in the December 21/28, 2002 issue of The Lancet (Vol. 360; 2018-25).
Novantrone (now marketed by Serono, Inc.) is administered via intravenous (into the vein) infusion every three months. Based on this European study involving 188 people for two years, the investigators showed that Novantrone can reduce the frequency of clinical relapses in those with secondary-progressive or worsening relapsing-remitting MS. It also delayed the appearance of new relapses, slightly improved or slowed progression of disability status of the treated individuals, and reduced the accumulation of new MRI-detected lesions in the brain. Additional studies of Novantrone are now underway.
Before the October 2000 FDA approval for use of Novantrone against worsening MS, this potent immune-suppressing agent was approved only for use in acute nonlymphocytic leukemia and for pain associated with certain forms of prostate cancer. It acts by inhibiting the proliferation (division) of cells, suppressing immune-system B cells and helper T cells, and modulating other immune cells and substances. Researchers believe that MS results when such components of the immune system attack both myelin, the fatty substance that insulates nerve fibers, and the nerve fibers themselves.
Investigation of Novantrone for MS began in the late 1980s with studies, supported in part by the National MS Society, in animal models suggesting the drug could improve MS-like disease.
A total of 188 individuals were randomly assigned to one of three groups: an inactive placebo group, a lower-dose (5 mg/m2) group, and a higher-dose (12 mg/m2) group. Participants had either worsening relapsing-remitting MS (experiencing progressive disability between acute attacks) or secondary-progressive MS (individuals whose disease began with clearly defined attacks, or relapses, with recovery, but has changed to a course of gradual progression of disability with or without attacks).Treatment was given by intravenous infusion every three months. The trial was conducted at multiple medical centers in Europe, and was double-blinded, meaning that neither the examining physicians nor the patients knew to which group they had been assigned.
The two-year study was designed to measure as its primary outcome Novantrone’s impact on a composite score of five clinical measures. These included change in disability status (measured by Expanded Disability Status Scale), change in ambulation, number of relapses, time to first relapse, and change in standardised neurological status score. Secondary outcomes included changes in MRI-detected lesions.
As a group, at the end of two years those on higher-dose Novantrone had experienced 74% fewer relapses and a significant delay of subsequent relapses compared to the placebo group. The drug also slightly improved or slowed progression of disability status of the higher-dose group. In addition, 110 participants received annual MRI scans. At the end of two years, fewer in the higher-dose treatment group had evidence of new, active (“enhancing”) lesions than those in the placebo group, and the treatment group had accumulated fewer “T2 weighted” lesions – which tend to be longer standing and indicative of more permanent patches of tissue damage.
Safety and Side Effects:
Over two years, higher-dose Novantrone was generally well tolerated. Common side effects included nausea (76%), mild hair loss (61%), urinary tract infections (32%), and menstrual disorders including amenorrhea (absence of menstrual period, in 25% of females). Novantrone can increase the risk for infection, because it decreases the number of protective white blood cells.
However, from its use as a chemotherapy agent, Novantrone is known to be to be associated with congestive heart failure and fatalities at high cumulative doses. This dose-related cardiac toxicity has been reported with Novantrone in cumulative doses exceeding 140 mg/m2. Because of this, participants in this trial were monitored before and during the trial for cardiac function. Although no clinically significant cardiac toxicity was seen in this relatively short MS trial, the cumulative dose of Novantrone in this study was less than 100 mg/m2 , well below that dose that has caused problems. For this reason, when the agent was approved by the FDA for use in worsening MS, specific recommendations were provided regarding dose levels, duration of treatment and for monitoring of cardiac function during treatment. And, recommendations for longer-term studies were made by the FDA.
A follow-up study tracking cardiac toxicity in persons with multiple sclerosis who received Novantrone therapy was recently published (Ghalie RG et al, Neurology 2002; 59(6):909-13). Two of 1,378 (0.15%) patients experienced congestive heart failure after Novantrone therapy. Seventeen of 779 (2.18%) patients who had been tested before and after therapy for [a specific measure of] cardiac function (left ventricular ejection fraction) had evidence of decreased cardiac function after therapy which was not clinically significant (did not cause any symptoms). This dysfunction tended to occur with higher cumulative doses.
Additional studies of Novantrone are now underway, including a long-term followup study to determine its lasting effects and potential adverse events; a study of Novantrone in primary-progressive MS (characterized by progression from disease onset with no acute attacks or remissions); and studies of Novantrone in combination with other agents, including Avonex, Copaxone, Betaseron, methylprednisolone, or a heart-protecting drug (dexrazoxane).
Use in MS:
Novantrone was approved by the U.S. FDA in October 2000 for reducing neurologic disability and/or the frequency of clinical relapses (attacks) in secondary progressive MS, progressive-relapsing MS and worsening relapsing-remitting MS. Novantrone has not been approved for the treatment of primary-progressive MS.
According to criteria laid out in the FDA’s approval of Novantrone for MS, the drug should only be used in those with normal cardiac function, once every three months at a dose of 12mg/m2. The lifetime cumulative dose is limited to 140 mg/m2. For most, this would mean that after about 8 to 12 doses over 2 to 3 years, no more drug should be taken. Cardiac monitoring is required. Prior to each dose of Novantrone, blood samples should be taken to check blood counts and liver function.
The FDA-approved package insert for Novantrone also contains a warning that a form of cancer, called secondary acute myelogenous leukemia, has occurred in persons with MS treated with Novantrone. This is thought to occur more commonly in persons who have been treated previously or in combination with other chemotherapy or radiotherapy. In a study of 1774 non-MS patients treated for breast cancer with Novantrone, usually in combination with radiotherapy or other cytotoxic agents, the risk of developing secondary leukemia was estimated at 1.1 in 100 (1.1%) after 5 years and 1.6 in 100 (1.6%) after ten years. The long-term risks specific to individuals with MS treated with Novantrone are currently not known. One purpose of the follow-up studies is to determine such risks.
Individuals concerned about the use of Novantrone to treat worsening
MS should consult their personal physicians. Additional information is
available at http://www.nationalmssociety.org/Meds-Mitoxantrone.asp.
© 2003 The National Multiple Sclerosis Society