Mitoxantrone in Multiple Sclerosis

By | January 27, 2015

Mitoxantrone () was developed in the 1970s and is an antineoplastic agent. It is an anthracenedione derivative related to the anthracyclins doxorubicine and daunorubicine. It interacts with topoisomerase-2, stabilizes its cleavable complex with DNA, thus prevents the ligation of DNA strands, and consecutively delays the cell-cycle progression. Mitoxantrone is used to effectively treat malignancies such as breast and advanced prostate cancer, lymphoma, and leukemia. Furthermore, in common with other antineoplastic agents, strong immunosuppressive properties of mitoxantrone have been observed providing a rationale for its use in autoimmune disorders.

Evidence Leading To The Approval Of Mitoxantrone For Use In Multiple Sclerosis

Mitoxantrone in Experimental Autoimmune Encephalomyelitis

In the 1980s, mitoxantrone was proven effective in both actively and passively induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Ridge et al. observed a dose-dependent inhibitory effect as determined by clinical evaluation and histopathology in rat EAE. Interestingly, mitoxantrone was 10 to 20 times more effective than cyclophosphamide in suppressing the development of EAE. Moreover, in an adoptive transfer model, encephalitogenic T-cells treated with mitoxantrone, prior to injection, were unable to induce the disease, indicating an inhibitory effect of mitoxantrone on T-cells. Clinical relapses were prevented or ameliorated.

Clinical Studies of Mitoxantrone in MS

In a number of small open trials, positive effects of mitoxantrone in multiple sclerosis were shown ().

In a randomized, magnetic resonance imaging (MRI)-controlled, but clinically unblinded and not placebo-controlled, trial in France and the United Kingdom, the effects of mitoxantrone were assessed in patients with very active MS, denned as frequent severe relapses without clinical remittance. Forty-two patients were randomized and received monthly infusions of either 20 mg mitoxantrone (irrespective of the body surface) plus 1 g methylprednisolone (methylprednisolone) or 1 g methylprednisolone alone for six months. The primary endpoint was the percentage of patients without new active MRI lesions. At study entry the percentages were: mitoxantrone plus methylprednisolone, 10%; methylprednisolone alone, 4.8%. After six months, the numbers were: mitoxantrone plus methylprednisolone, 90%; methylprednisolone alone, 31% (P < 0.001).

In an Italian trial, the efficacy of mitoxantrone was assessed in 51 patients with relapsing-remitting (RR) multiple sclerosis. Inclusion criteria were an expanded disability status scale (EDSS) between two and five and at least two relapses within the previous two years. The patients were randomized and received either mitoxantrone (8 mg / m2 body surface) or placebo. Clinical assessment was performed by blinded physicians. The primary endpoint was the percentage of patients with clinical progression, denned as an expanded disability status scale increase by one point. After 24 months of observation, 9 out of 24 patients with placebo (37%) and 2 out of 27 patients with mitoxantrone (7%) deteriorated clinically by one expanded disability status scale point (P = 0.02). Regarding the secondary endpoints, mitoxantrone was partially superior to placebo.

A comparative double-blind trial of mitoxantrone (13 infusions of 12 mg / m2 body surface) versus methylprednisolone (13 infusions of 1 g, both groups over 32 months) in 49 patients with secondary progressive (SP) MS, performed in Belgium, revealed a significant improvement of the expanded disability status scale and a significant decrease of the total number of gadolinium-enhancing lesions in the mitoxantrone group.

The largest phase III study, thus far, is the mitoxantrone in multiple sclerosis (MIMS) study, which led to approval for the treatment of multiple sclerosis number of regulatory authorities. The MIMS study was a randomized, placebo-controlled, investigator-blinded multicenter trial in patients with worsening relapsing-remitting multiple sclerosis and SPMS. One hundred and ninety four patients with an expanded disability status scale between three and six were randomized and divided into three groups: (i) mitoxantrone 12mg / m2 body surface, (ii) mitoxantrone 5mg / m2, and (iii) placebo (methylene blue). All patients received mitoxantrone or placebo intravenously every three months for two years. The primary study endpoint was a multivariate analysis of five different clinical parameters (change from three neurological baseline scores including expanded disability status scale after 24 months, time for first treated relapse, and number of relapses treated with steroids). After two years, 188 patients still participated in the study. In all five parameters, the mitoxantrone 12mg / m2 group was significantly superior compared to the other groups. Progression of disability and relapse rate were significantly reduced. This therapeutical effect was still measurable even after 12 months of final infusion. In a subgroup of 110 patients, in addition to the clinical investigation, MRI assessment was performed and analyzed in a central laboratory. Significantly fewer patients receiving 12mg / m2 mitoxantrone demonstrated enhancing lesions at 24 months relative to placebo (0% vs. 15.6%, P = 0.02). The mean increase in the number of T2-weighted lesions was 0.29 in 12mg / m2 mitoxantrone and 1.94 in placebo recipients (P = 0.zzz). In both mitoxantrone groups, a significant reduction of new lesions and a reduced burden of disease were observed.

Current Clinical Aspects Of Mitoxantrone

Indication — Which Patients Should Be Treated?

Several national and international medical advisory boards to multiple sclerosis societies recommend the use of mitoxantrone in patients with relapsing-remitting multiple sclerosis who have frequent relapses and incomplete remissions and those with SPMS having rapid progression (by at least one expanded disability status scale point per year). Decision to use the treatment should be given by experienced neurologists at clinical multiple sclerosis centers. Although the following treatment recommendations reflect expert opinions, have no definite evidence base, and three groups of multiple sclerosis patients are recommended for treatment with mitoxantrone ():

1. relapsing-remitting multiple sclerosis patients with two or more relapses per year, incomplete remission (EDSS >3) and insufficient response to IFN-β or glatiramer acetate;

2. SPMS patients with marked progression of disability (> 1 expanded disability status scale point per year) and / or high relapse rate (>2 relapses per year); and

3. SPMS patients with rapid progression (>1 expanded disability status scale point per year) without relapses.

According to the primary endpoints of the different clinical studies with mitoxantrone, the therapeutic goal is the clinical and MRI stabilization of the disease. The characterization criteria of responders or nonresponders and the treatment duration before the evaluation of a clinical response are not yet defined. A suggested, but not evidence-based, marker to detect a clinical nonresponder is the deterioration of one expanded disability status scale point after one year of treatment.

For primary progressive (PP) multiple sclerosis patients treatment options are limited. For mitoxantrone, efficacy in PPmultiple sclerosis is currently addressed in clinical trials, although the results presented thus far are disappointing.

Dosage and Duration of Treatment

According to regularly body approvals based on the clinical trials, the currently recommended mitoxantrone dose is 12mg / m2 body surface administered intravenously every three months. In some countries, the dosage regimen of the French-British trial is approved, i.e., 20 mg monthly for six months, irrespective of the body surface. Patients with aggressive multiple sclerosis can be considered for treatment with an induction therapy with mitoxantrone 10 to 12mg / m2 monthly for the first three months followed by the regular trimester scheme. The optimal dosage regimen remains to be evaluated and is currently being assessed in a European clinical trial comparing three different doses (5, 9, and 12mg / m2 body surface).

Practical Guidelines

Before onset of therapy, a number of laboratory exams are recommended including a pregnancy test (during pregnancy and nursing, mitoxantrone is contraindicated), chest X-ray, electrocardiography, and echocardiography with quantitative assessment of the left ventricular ejection fraction (LVEF). Due to the risk of infertility, male patients should be offered the opportunity to cryopreserve their sperms. Antiemetic protection in parallel to the mitoxantrone infusion may be helpful. The most clinically relevant interactions of mitoxantrone are with phenytoin (decreased plasma concentration) and angiotensin converting enzyme inhibitors (increased bone marrow toxicity). Due to the increased risk of infections, patients treated with mitoxantrone should not receive live vaccines. Patients with hepatic disturbances require reduced doses of mitoxantrone (), whereas for patients with renal disturbances there are no restrictions.

Safety and Tolerability

The MIMS trial and preceding studies exhibited a generally good safety profile of mitoxantrone (). Adverse events were rare and mild to moderate. However, long-term follow-up data are still pending for finally evaluating the safety profile of mitoxantrone. To this end, a large open-label multicenter study of mitoxantrone in 509 multiple sclerosis patients with a five-year observation period and a broad number of outcome measures (Registry to Evaluate Novantrone® Effects in Worsening MS) is currently underway.

Cardiotoxicity

Treatment with mitoxantrone is restricted to a cumulative total life dose of 140 mg / m2 body surface, i.e., when using the standard dose of 12mg / m2, the treatment must be discontinued after approximately 12 infusions. The reason for this restriction is the increased risk of an irreversible congestive cardiomyopathy beyond the threshold of 140 mg / m2 body surface as observed in cancer patients treated with mitoxantrone. A recently published retrospective study has investigated the risk of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis. In this study, data obtained from 1378 patients from three clinical trials were analyzed: the MIMS trial (124 patients), a French open multi-center trial (802 patients), and a retrospective German trial (452 patients). The mean treatment duration was 29 months; the mean cumulative dose was 61 mg / m2 body surface. One hundred and forty one patients had received a cumulative mitoxantrone dose of more than 100 mg / m2 body surface. Two of the 1378 patients developed a lethal congestive heart failure after onset of therapy with mitoxantrone. One of the two patients had received a cumulative dose of 162 mg / m2 body surface. The other patient had received only one single dose of 9 mg / m2; after one year, her LVEF was > 50 %; four years after treatment with mitoxantrone, she died of congestive heart failure, the relationship of which to the previous mitoxantrone therapy remains uncertain. Seven hundred and seventy-nine patients examined by echocardiography before and during treatment. In 17 of these 779 patients, a reduction of the LVEF below 50% was observed. All 17 patients had received a cumulative dose of more than 100 mg / m2. More recently, one more mitoxantrone-treated multiple sclerosis patient with congestive heart failure was documented in a case report.

The pathomechanisms of the mitoxantrone-associated cardiotoxicity remain elusive. Proposed mechanisms are based on (i) free radicals, (ii) oxidative stress, (iii) altered function of myocardial adrenergic receptors, (iv) disturbed calcium transport in the cardiac sarcolemma, (v) lipid peroxidation, and (vi) cytokines such as tumor necrosis factor (TNF)-a or interleukin (IL)-2.

Currently, several strategies are being pursued to circumvent the problem of mitoxantrone-associated cardiotoxicity. These include giving pulses of reduced doses of mitoxantrone in order to prolong its application. Furthermore, animal data has revealed that the combination of mitoxantrone with the cardioprotector dexrazox-ane may be useful to ameliorate or even prevent the mitoxantrone-associated cardiotoxicity. Interestingly, in a recent publication, dexrazoxane was shown to increase the efficacy of mitoxantrone in EAE. An alternative would be the development of other anthracenedione derivatives with lower cardiotoxicity.

Therapy-Related Acute Leukemia

Mitoxantrone and other topoisomerase-2 inhibitors have been reported to induce acute leukemia. In the retrospective study with 1392 multiple sclerosis patients mentioned above, one case was observed (0.07%). Other seven case reports have been published. Retrospectively, Voltz et al. calculated a relative risk of 0.21%.

Other Adverse Events

Mitoxantrone is generally well tolerated. For further adverse events documented in the MIMS trial, see Table 4. Secondary amenorrhea occurs in up to 10% of female patients treated with mitoxantrone. Paravasation of the compound has to be strictly avoided as tissue damage may occur. In case of accidental paravasation, the infusion should be immediately interrupted, and the patient should receive steroids (hydrocortisone, 100 mg intravenously and 100 mg fractionated subcutaneously into the paravasal space).

Conclusions

For treatment of multiple sclerosis, immunosuppressive drugs including mitoxantrone have been used off-label for decades. Approval of immunomodulatory agents in the mid-1990s shifted the market towards interferon-p () and glatiramer acetate (). However, worsening forms of relapsing-remitting multiple sclerosis and especially SPMS could not be treated satisfactorily with these new therapeutics. Thus, mitoxantrone that has immunosuppressive and also apparently immunomodulatory effects returned to the focus of interest which — based on its proven efficacy in phase III trials — has recently led to its approval.

The, thus far, positive experiences with mitoxantrone open further questions:

  1. 1. Can dose and frequency of administration be optimized?
  2. 2. Can the dose, due to the cardiotoxicity, be reduced after an induction phase without impairing the clinical effect?
  3. 3. Is there a rationale for a combination of mitoxantrone with immunomodulatory agents?
  4. 4. What is the optimal subsequent therapy after discontinuation with mitoxantrone?
  5. 5. What are the treatment options for clinical nonresponders to mitoxantrone? In this circumstance, is there a rationale for the use of other immunosuppres-sants such as azathioprine or cyclophosphamide?

These and other questions are matter of intensive discussion. First preclinical and clinical studies including combination trials of mitoxantrone plus IFNβ, glatiramer acetate, or dexrazoxane have been initiated to address some of these aspects.