Cyclophosphamide May Be Low-cost Option for Refractory Patients, Study Says

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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Cyclophosphamide, a medicine with immunosuppressant abilities, may be a potential short-term alternative treatment for refractory — or difficult to treat — myasthenia gravis (MG), especially in lower-income countries, a small study from Mexico reports.  

The study, “Intravenous cyclophosphamide monthly pulses in refractory myasthenia gravis,” was published in The Journal of Neurology.

Around 10% of all MG cases are refractory, meaning they are resistant to conventional treatments, including corticosteroids such as prednisone, and steroid-sparing immunosuppressant therapies (ISTs).

“Refractory MG [myasthenia gravis] generates significant disability, frequent hospitalizations in emergency services and intensive care units with systemic complications and significant increase in mortality,” the scientists wrote.

For these patients, alternative therapies — such as plasma exchange (PLEX) or intravenous immunoglobulin G (IVIg) — are available but they are costly and provide only temporary relief.

Rituximab has also been shown to be effective in treating MG with a lower rate of side effects, but it too is costly. With other expensive treatments, it is unavailable or inaccessible to patients in poorer countries or low-income areas within countries like Mexico.

Cyclophosphamide (brand names include Cytoxan and Neosar) was developed as a chemotherapy drug, but later found to also have immunosuppressant effects, or an ability to suppress the immune system.

The medicine is used to treat a variety of conditions. Reasonably priced and widely available, it has been used in refractory MG but with controversial results.

“[T]he use of CYC [cyclophosphamide] is common in our practice, frequently as a substitute immunosuppressant in different pathologies [diseases],” the scientists said.

The team of researchers at the Instituto Nacional de Neurología Y Neurocirugía Manuel Velasco Suarez set out to determine the efficacy of cyclophosphamide in refractory MG patients being followed at their institute.

In total, 139 MG patients were treated at this center since 2010. Of them, 16 (11.5%) had refractory MG.

Researchers focused their study on the eight people in this refractory group (seven women and one man, median age 34.8) given monthly pulses of cyclophosphamide at high dose (30–50 mg/kg) for at least six months.

Before undergoing the treatment, three patients had a myasthenic crisis that required mechanical respiratory support. All had been previously treated with steroids, and given azathioprine (AZT) as an add-on immunosuppressive therapy. One person underwent a thymectomy, but the others were not considered to be healthy enough for the procedure.

Seven patients (87.5%) received at least six cycles of cyclophosphamide, and one three cycles. All were followed for at least seven months.

The therapy’s efficacy was measured using the Osserman scale under which significant improvement is defined as a reduction of at least one point, and the Myasthenia Gravis Composite (MGC) scale in which a three-point change is considered meaningful.

According to the Osserman scale, 75% of these patients showed clinical improvements and remained stable at six months of high-dose cyclophosphamide treatment. The other 25% had stable disease at six months, one patient relapsed. The score in the MGC scale significantly decreased from a median of 12.25 to 4.8.

These difficult-to-treat patients remained relapse free for a median of 9 months.

“Although previous series also showed a significant clinical improvement maintained for several years, unfortunately in our group the relapse was within 12 months,” the researchers wrote, “and in some of these patients it was necessary to start other concomitant immunomodulatory agents.”

However, they added that their study’s goal — that  of demonstrating an adequate response to monthly cyclophosphamide doses — was met, although benefits were not sustained for a longer time that about nine months.

Adverse effects were seen in two patients, and included leukopenia (decrease in the number of white-blood cells) and gastrointestinal symptoms, which were resolved.

“It is also important to bear in mind that in many [previous] studies … the sustained effect of CYC may also be related to thymectomy which is associated with the maintenance of therapeutic benefits over longer periods,” the team added.

One limitation to this study’s findings is its small size.

Still, considering that cyclophosphamide was effective in reducing symptoms in refractory MG patients and without severe side effects at high dose over the short term, “its use could be considered as induction therapy in environments where socioeconomic inequalities and limited resources persist,” the researchers concluded.