Ten-year follow-up after mitoxantrone induction for early highly active relapsing-remitting multiple sclerosis: An observational study of 100 consecutive patients.

BACKGROUND: Six monthly courses of mitoxantrone were approved in France in 2003 for patients with highly active multiple sclerosis (MS). OBJECTIVE: To report the 10-year clinical follow-up and safety of mitoxantrone as an induction drug followed by maintenance therapy in patients with early highly active relapsing-remitting MS (RRMS) and an Expanded Disability Status Scale (EDSS) score<4, 12months prior to mitoxantrone initiation. METHODS: In total, 100 consecutive patients with highly active RRMS from the Rennes EDMUS database received monthly mitoxantrone 20mg combined with methylprednisolone 1g for 3 (n=75) or 6months (n=25) followed by first-line disease-modifying drug (DMD). The 10-year clinical impact was studied through clinical activity, DMD exposure, and adverse events. RESULTS: Twenty-four percent were relapse-free over 10years and the mean annual number of relapses was 0.2 at 10years. The mean EDSS score remained significantly improved for up to 10years, changing from 3.5 at mitoxantrone initiation to 2.7 at 10years. The probability of disability worsening and improvement from mitoxantrone initiation to 10years were respectively 27% and 58%, and 13% converted to secondary progressive MS. Patients only remained untreated or treated with a first-line maintenance DMD for 6.5years in average. In our cohort, mitoxantrone was generally safe. No leukemia was observed and six patients developed neoplasms, including 4 solid cancers. CONCLUSION: Monthly mitoxantrone for 3 or 6months, followed by maintenance first-line treatment, may be an attractive therapeutic option for patients with early highly active RRMS, particularly in low-income countries.

Inaugural tumor-like multiple sclerosis: clinical presentation and medium-term outcome in 87 patients.

BACKGROUND: Tumefactive demyelinating lesions of the central nervous system can be the initial presentation in various pathological entities [multiple sclerosis (the most common), Balo's concentric sclerosis, Schilder's disease and acute disseminated encephalomyelitis] with overlapping clinical presentation. The aim of our study was to better characterize these patients. METHODS: Eighty-seven patients (62 women and 25 men) from different MS centers in France were studied retrospectively. Inclusion criteria were (1) a first clinical event (2) MRI showing one or more large demyelinating lesions (20 mm or more in diameter) with mass-like features. Patients with a previous demyelinating event (i.e. confirmed multiple sclerosis) were excluded. RESULTS: Mean age at onset was 26 years. The most common initial symptoms (67% of the patients) were hemiparesis or hemiplegia. Aphasia, headache and cognitive disturbances (i.e. atypical symptoms for demyelinating diseases) were observed in 15, 18 and 15% of patients, respectively. The mean largest diameter of the tumefactive lesions was 26.9 mm, with gadolinium enhancement in 66 patients (81%). Twenty-one patients (24%) had a single tumefactive lesion. During follow-up (median time 5.7 years) 4 patients died, 70 patients improved or remained stable and 12 worsened. 86% of patients received initial corticosteroid treatment, and 73% received disease-modifying therapy subsequently. EDSS at the end of the follow-up was 2.4 ± 2.6 (mean ± SD). CONCLUSION: This study provides further evidence that the clinical course of MS presenting with large focal tumor-like lesions does not differ from that of classical relapsing-remitting MS, once the noisy first relapsing occurred.

Is the Choosing Wisely® campaign model applicable to the management of multiple sclerosis in France? A GRESEP pilot study.

BACKGROUND: Launched in the US in 2012, Choosing Wisely® is a campaign promoted by the American Board of Internal Medicine (ABIM) Foundation with the goal of improving healthcare effectiveness by avoiding wasteful or unnecessary medical tests, treatments and procedures. It uses concise recommendations produced by national medical societies to start discussions between physicians and patients on the relevance of these services as part of a shared decision-making process. The Multiple Sclerosis Focus Group (Groupe de Reflexion Autour de la Sclérose en Plaques; GRESEP) undertook a pilot study to assess the relevance and feasibility of this approach in the management of multiple sclerosis (MS) in France. METHODS: Recommendations were developed using the formal consensus method from the guidelines of the French National Health Authority (HAS). A steering committee selected the themes and drafted concise evidence reviews. An independent rating group then assessed these recommendations for clarity, relevance and feasibility. RESULTS: Seven recommendations were accepted: (1) avoid systematic ordering of multimodal evoked potential studies for diagnosing MS; (2) do not treat MS relapses with low-dose oral corticosteroids; (3) when treating MS relapse with high-dose corticosteroids, the systematic use of the intravenous route is unnecessary if the oral route can be used; (4) systematic hospitalization is not necessary for treating MS relapse with high-dose corticosteroid therapy, particularly if the oral route is used, except for the first treated relapse and the presence of exclusion or non-eligibility criteria; (5) in the absence of clinical signs or symptoms of urinary infection, avoid systematic screening with urine microscopy and culture before the administration of corticosteroid therapy for MS relapse in patients using intermittent self-catheterization; (6) avoid antibiotic treatment of clinically asymptomatic MS patients using intermittent self-catheterization, even if urine microscopy and culture reveal the presence of microorganisms; and (7) avoid introducing symptomatic drug treatment for MS-related fatigue. CONCLUSION: This pilot study, the first of its kind in France, has demonstrated the relevance and feasibility of adapting the Choosing Wisely® model to MS by practitioners specializing in the disorder. However, the acceptability of these recommendations by other practitioners in other specialist fields as well as their impact on everyday clinical practices now need to be studied.

Long-term safety profile of mitoxantrone in a French cohort of 802 multiple sclerosis patients: a 5-year prospective study.

BACKGROUND: From 2001, a French multicentre study was conducted prospectively in a large cohort of MS patients and annually updated up to at least 5 years after initiation of MITOX therapy. OBJECTIVE: To determine long-term safety profile of mitoxantrone (MITOX) in multiple sclerosis (MS). METHODS: Eight hundred and two patients from 12 MS centres (308 relapsing-remitting, 352 secondary progressive and 142 primary progressive) received MITOX monthly for 6 months (87%) or every 3 months (13%). Patients underwent clinical and haematologic evaluations before every MITOX infusion and every 6-12 months up to 5 years after MITOX start. Echocardiograms were performed at the start and end of MITOX and up to 5 years after. RESULTS: The cohort was followed for 5354 patient-years (mean). One out of 802 patients (0.1%) presented with acute congestive heart failure and 39 out of 794 patients (4.9%) presented with asymptomatic left ventricular ejection fraction reduction under 50% (persistent in 11 patients (28%), transient in 27 patients (69%), on the last scan at year 5 in 1 patient). Two cases of therapy-related leukaemia (0.25%) were detected 20 months after MITOX start (one death and one with 8 years confirmed remission). Of the 317 women treated before the age of 45, 17.3% developed a persistent age-dependant amenorrhea. CONCLUSION: This large cohort with at least 5 years of follow-up provided good insights into the long-term safety profile of MITOX in MS.

[Use of mitoxantrone in early multiple sclerosis with malignant disease course. Observational study in 30 patients with clinical and MRI outcomes after one year]. / Utilisation de la mitoxantrone dans les formes malignes inaugurales de sclérose en plaques. Etude observationnelle de 30cas. Evaluations cliniques et IRM à un an.

INTRODUCTION: In an observational multicenter study, we analyzed retrospectively 30 patients with malignant form of multiple sclerosis (MS) treated with mitoxantrone the year following the first neurological event. METHODS: The 30 patients were selected according to Weinshenker criteria of malignant MS (either a "catastrophic" relapse or a quickly aggressive form). We compared clinical and MRI findings the year before with the year following mitoxantrone onset treatment: annualized relapse rates (ARR), EDSS score and percentage of patients with gadolinium enhancing lesions on MRI. RESULTS: A total of 87 relapses were observed in the 5.7 months before and 10 during the year following onset of mitoxantrone treatment. The ARR decreased by 95% (6.0+/-2 before and 0.3+/-0.7 after). Twenty-four patients (80%) were relapse-free one year after onset of mitoxantrone treatment. The EDSS score improved in 87% of MS patients and the mean EDSS decreased by 1.9. Ninety-seven percent had at least gadolinium enhancing lesions before the start of mitoxantrone treatment as compared to 17% after. CONCLUSION: In our experience, mitoxantrone had a rapid and strong impact on the malignant forms of MS with a short disease duration. In this MS subgroup, mitoxantrone should be considered as an early treatment option.

Mitoxantrone in the treatment of multiple sclerosis.

Mitoxantrone is useful for the treatment of cancer and MS and, as with other chemotherapeutic agents, many studies have examined its tolerability. The suitability of mitoxantrone in MS is particularly interesting because of its role in treating various stages of the disease. Evidence shows that mitoxantrone could be a first-line treatment for malignant forms of MS, and a second-line drug in relapsing-remitting or secondary progressive MS that is unresponsive to interferon beta-1a, -1b or glatiramer acetate. Mitoxantrone should, however, be restricted to patients with demonstrable inflammatory disease activity, and should only be prescribed by neurologists with previous experience in both MS and mitoxantrone therapy. This review examines the properties of mitoxantrone, its tolerability, and discusses its suitability for treating various forms of MS, referring to several important studies.

[Sinus cavernous syndrome caused by isolated aspergillosis of the sphenoid sinus]. / Syndrome du sinus caverneux par aspergillose isolée du sinus sphénoïdal.

Isolated aspergillosis of the sphenoid sinus is a rare condition that is frequently diagnosed at a late stage because of its nonspecific and varying symptomatology. We report the case of a 75-year-old diabetic woman with a long history of retroorbital pain before she developed a subacute cavernous sinus syndrome. Neuroimaging including CT scan and MRI suggested a malignant tumor involving the sphenoid sinus but the diagnosis of aspergillosis was made intraoperatively and by histopathological examination. Soon after surgical drainage of the sphenoid sinus and systemic anti-fungal drug therapy, both retroorbital pain and cavernous sinus syndrome had completely resolved. This case emphasizes the fact that invasive isolated sphenoid sinus aspergillosis must be considered in the list of lesions causing sinus cavernous syndrome.

A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis.

To evaluate the incidence of therapy-related acute leukaemia (t-AL) after single-agent mitoxantrone (MITO) treatment, we reviewed medical records of patients in three studies of single-agent MITO therapy for multiple sclerosis (MS) and existing literature on MITO therapy in MS, leukaemia, and solid tumors. Of 1378 MITO recipients in the three MS studies (mean cumulative dose of 60 mg/m2 and mean follow-up of 36 months), one patient had t-AL, an observed incidence proportion of 0.07% [95% confidence interval (CI) = 0.00-0.40%]. There were no cases of t-AL in published reports of nine additional studies of single-agent MITO therapy for MS. There was one published case report of acute promyelocytic leukoemia detected five years after initiating MITO therapy for MS. The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS. Although these observations provide preliminary reassurance, extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk of t-AL after MITO therapy for MS.

Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS.

The authors report a patient with severe secondary progressive MS who responded to mitoxantrone but developed a fatal acute myeloblastic leukemia 15 months after completion of mitoxantrone therapy. Therapy-related acute leukemia (TRAL) in relation with mitoxantrone is rare; this patient was the first case among a cohort of 802 French MS patients treated with mitoxantrone. Nevertheless, this case stresses the need to further evaluate the long-term risk of TRAL in patients with MS who receive mitoxantrone.