Use of cyclophosphamide regimen found effective in hard-to-treat MG
Treatment given over 6 months, followed by maintenance immunotherapy
Short-term use of cyclophosphamide — given in six monthly cycles, followed by maintenance immunotherapy — markedly reduced the clinical severity of hard-to-treat myasthenia gravis (MG), according to a study by researchers in Australia and the U.K.
The therapeutic response seen among patients also allowed a reduction in the use of supportive therapies, such as steroids, with the researchers noting that cyclophosphamide treatment “offers genuine remission induction potential” in people with MG.
Despite concerns of toxicity associated with cyclophosphamide, the treatment was well tolerated, with most side effects being considered mild, the team also noted.
“We suggest cyclophosphamide should be considered for rapid remission induction, corticosteroid reduction and long-term freedom from recurrent injectable therapies in selected patients,” the researchers wrote.
Their study, titled “Induction cyclophosphamide with maintenance immunosuppression in high-risk myasthenia gravis: long-term follow-up and safety profile,” was published in the Journal of Neurology, Neurosurgery and Psychiatry.
Investigating short-term cyclophosphamide use in refractory MG
MG is caused by self-reactive antibodies that target and damage components of the neuromuscular junction — the site where nerves connect to the muscles they control. In most cases, these antibodies target the acetylcholine receptor, or AChR, a protein on muscle cells that responds to nerve signals to coordinate muscle contraction.
Despite advancements in MG treatment, including medications to suppress immune responses or improve AChR-related function, some patients experience refractory or hard-to-treat MG, meaning their disease fails to respond to treatment.
Cyclophosphamide (sold as Cytoxan and also available as generics) was originally developed as a cancer therapy, but was later found to suppress the immune system and thus have the potential to be used to manage autoimmune diseases. But due to side effects associated with its use, cyclophosphamide is generally reserved for people with refractory MG.
To date, however, few studies have investigated the use of cyclophosphamide in refractory MG due to safety concerns and the lack of standardized post-treatment options to sustain its clinical benefits.
To address this, a team of researchers conducted a retrospective review to assess the long-term clinical outcomes of refractory MG patients treated with cyclophosphamide, followed by maintenance immunotherapy.
Refractory MG was defined as disease that was poorly controlled despite the use of corticosteroids, disease-blocking therapies, such as plasma exchange (PLEX) or intravenous immunoglobulin (IVIg), and at least one immunosuppressive therapy.
The team examined data from 31 such patients, with follow-ups ranging from five months to 11 years. The data involved 19 men and 12 women, ages 32 to 83.
Nearly all of the patients (93.5%) tested positive for self-reactive antibodies against AChR, and about half (45.2%) had tumors in the thymus gland, called thymoma. Such tumors are thought to drive the production of disease-driving antibodies. More than half of these patients — 17 or 54.8% — had their thymus surgically removed in a thymectomy.
All patients also had various side effects related to the corticosteroid prednisolone, including weight gain, osteoporosis, high blood sugar, and psychiatric issues.
Treatment reduced clinical severity, use of supportive therapies
Cyclophosphamide was infused intravenously, or directly into the bloodstream, every four weeks for six cycles. Maintenance immunotherapy with mycophenolate mofetil (sold as CellCept and others), azathioprine (sold as Imuran and others), or methotrexate (sold as Jylamvo and others) was started four to six weeks after the final cycle.
Disease severity was assessed with the MG Composite (MGC) scale, in which higher scores indicate more severe disease. MGC data were recorded before cyclophosphamide, 10-14 days after each treatment cycle, and at the last follow-up visit.
The results showed that 87% of the patients “demonstrated dramatic clinical improvement” after cyclophosphamide treatment, according to the researchers. Median MGC scores dropped by more than 50% after the third treatment cycle. Overall, the median MGC score of 14 before treatment was reduced to 1 after treatment.
“This is a remarkable effect within this patient cohort given all patients had moderate-to-severe disease prior to [cyclophosphamide] treatment,” the team wrote.
[More than 97% of patients] demonstrated dramatic clinical improvement. … This is a remarkable effect within this patient cohort given all patients had moderate-to-severe disease prior to [cyclophosphamide] treatment
Clinical benefits also drove a reduction in the use of prednisolone, PLEX, and IVIg. At the last follow-up, 11 patients had stopped taking prednisolone, while 20 remained on daily doses ranging between 1.25 and 15 mg. PLEX was stopped in 13 of 21 cases (62%), and IVIg was halted in 11 of 20 cases (55%).
Four participants (13%) didn’t respond to cyclophosphamide, as indicated by no improvements in MGC scores.
Due to the side effects associated with cyclophosphamide, all patients underwent frequent monitoring for cytopenia, marked by low levels of red blood cells, white blood cells, or platelets. Data showed cytopenias were mild, with no patients needing support therapy.
A total of 12 adverse events involving nine patients were recorded. Most of them were mild and included low white blood cell counts, or asymptomatic lymphopenia, and nausea. Three severe adverse events of infections that required hospitalization and intravenous antibiotics were also reported.
“We propose [cyclophosphamide] with subsequent routine initiation of a corticosteroid-sparing maintenance agent should be considered as an efficacious therapy to achieve remission in a considered cohort of AChR MG patients,” the researchers wrote.
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