Q&A with Dr. Allen DeSena: Intravenous Cyclophosphamide for Transverse Myelitis

What is cyclophosphamide?

Cyclophosphamide (a.k.a. Cytoxan) is a chemotherapy that has been more traditionally used for certain forms of cancer.  It actually works through one of its metabolites – it’s metabolized through the liver – to add a certain molecule to DNA.  In doing this, the cells are prone to dying, and it tends to affect the immune cells preferentially, so it has an immunosuppressive effect. The dose of cyclophosphamide varies depending on why it is used – usually at high doses for cancer and much lower doses for conditions like transverse myelitis.

Why is it used for transverse myelitis? 

Because of its immunosuppressive effect, and the prevailing theory that transverse myelitis is caused by an overactive immune system that has become “confused” by attacking its own spinal cord, these have led to the consideration of using it for transverse myelitis.  In addition, it has had some particular notable success in other autoimmune diseases, specifically systemic lupus erythematosus (SLE or called just ‘lupus’ commonly) and Sjogren’s disease.  Furthermore, these are two diseases that can rarely present with transverse myelitis also.

When do you consider using cyclophosphamide?

We will typically use intravenous cyclophosphamide after the patient fails to respond or has a poor response to intravenous steroids and/or if they fail less aggressive therapies such as plasma exchange or intravenous immunoglobulin.  We have used it for transverse myelitis and acute disseminated encephalomyelitis.  Furthermore, although there is a case report about a patient with neuromyelitis optica (NMO) responding well to cyclophosphamide, there are other reports of patients with NMO that have tended not to respond well to it.  So, we typically have not used it if we have either a strong suspicion of NMO.

Are there studies in which cyclophosphamide has been used for transverse myelitis?

There are several case reports and large case series of cyclophosphamide use.  Many of these, as mentioned above, discuss cyclophosphamide with SLE or Sjogren’s-related myelitis.  There is a large retrospective review of cyclophosphamide usage in transverse myelitis that showed suggestion of benefit in patients that had a more severe transverse myelitis (defined as being labeled ASIA A – which is a spinal cord injury classification in which the patients have complete sensory and motor loss and bladder/bowel function impairment).  The main limitation of this study was that the transverse myelitis patients were not all idiopathic, some were later diagnosed with NMO, MS, etc.  In addition, there was no benefit noted in this retrospective review with cyclophosphamide’s effect on patients with less severe transverse myelitis.  There have been no clinical trials with cyclophosphamide and transverse myelitis or acute disseminated encephalomyelitis.  A list of cyclophosphamide and myelitis articles will be included at the end of this article.

How quickly does cyclophosphamide work?

Cyclophosphamide does not work immediately.  It takes about 10-14 days to reach peak effect.  It will be out of your system in about a month.

What are the side effects?

The main side effects we see are nausea, vomiting and loss of appetite around the time of the infusion, although we give medications to help prevent this.  One of the concerning side effects during the infusion is an increased risk for hemorrhagic cystitis – a term for bleeding from the wall of the bladder into the urine.  This occurs because one of the metabolites of cyclophosphamide irritates the cells in the bladder wall, but cyclophosphamide is usually given with a medication called MeSNa (2-mercaptoethane sulfonate Na), which binds up that metabolite and dramatically reduces the risk of this complication.  There is always a concern for an infusion reaction too, but, again, this is rarely seen.  Patients are at an increased risk for infections after an infusion, but these are rare.  For this reason, we typically recommend only common sense-type precautions such as regular hand-washing, avoidance of people known to be sick, and avoiding sharing drinking glasses and similar such things.  We also may see some mild hair thinning at the doses we use, but profound hair loss is very rare.  In addition, we can see changes in the blood counts after it reaches peak effect, and we typically recommend some blood work about 2 weeks after the cyclophosphamide is completed.  In a large study of patients on regular cyclophosphamide doses over many months, the incidence of infections were about 20%, but the incidence of infections requiring a hospital visit was only about 8%.  These were patients getting regular cyclophosphamide infusions over many months, whereas in TM we typically only give one dose.  Theoretical long-term side effects are potential risks for future malignancies (cancers), infertility (both for men and women).  Nearly all of our safety data for cyclophosphamide comes from studies of its use in cancer, and patients are getting much higher doses of it for much longer.

What have you seen with cyclophosphamide in your experience? 

It is difficult to give percentages about responses to cyclophosphamide for either transverse myelitis or acute disseminated encephalomyelitis, but we have seen a few patients that appeared to have achieved more significant recovery following their cyclophosphamide infusion than we would have otherwise expected.

Do all medical centers and hospitals have access to this medication?

Most hospitals and centers that see children with transverse myelitis likely do have access to this medication; however, some neurologists and other specialists may not be as familiar with it as in some other places and may be hesitant to offer it as a next option.  We would always encourage families with children or other family members with either TM or ADEM to ask their doctors about other medication and treatment options should there continue to be significant neurologic deficits after standard treatment has runs its course.  The decision to use Cytoxan has to be individualized to each patient’s situation. The TMA is also a great resource for helping to direct families to the medical centers with the most TM and ADEM experience.

References

Ammouri W, Mezalek ZT, Harmouche H, Aouni M, Adnaoui M, and Maaouni A.  “Myelitis Complicating Systemic Lupus Erythematosus: Successfully Treated with Corticosteroids and Cyclophosphamide.” South Med J.  2009; 102; 744-745.

Bichuetti DB, Oliveira EML, Boulos FC, and Gabbai AA.  “Lack of Response to Pulse Cyclophosphamide in Neuromyelitis Optica: Evaluation of 7 Patients.” Arch Neurol.  2012; 69; 938-939.

Birnbaum J and Kerr DA.  “Optic neuritis and recurrent myelitis in a woman with systemic lupus erythematosus.”  Nat Clin Practice.  2008; 4; 381-386.

Carter D, Olchovsky D, Langevitz HYP, and Ezra D.  “Simultaneous deep vein thrombosis and transverse myelitis with negative serology as a first sign of antiphospholipid syndrome: a case report and review of the literature.” Clin Rheumatol. 2006; 25; 756–758.

Gadze ZP, Hajnsek S, Basic S, Sporis D, Pavlisa G, and Nankovic S.  “Patient with neuromyelitis optica and inflammatory demyelinating lesions comprising whole spinal cord from C2 level till conus: case report.” BMC Neurol; 2009; 56.

Greenberg BM, Thomas KP, Krishnan C, Kaplin AI, Calabresi PA, and Kerr DA.  “Idiopathic transverse myelitis: Corticosteroids, plasma exchange, or cyclophosphamide.”  Neurology; 2007; 68; 1614-1617.

Krishnan C, Kaplin AI, Graber JS, Darman JS,  and Kerr DA.  “Recurrent transverse myelitis following neurobrucellosis: Immunologic features and beneficial response to immunosuppression.” J NeuroVirol; 2005; 11; 225–231.

Misra AK, Mishra SK, Eigen AC, and Tourtcllotte WW.  “Successful immunosuppressive therapy for HTLV-I associated myelopathy.”  J Neurolog Science.  1994; 122; 155-156.

Neumann-Andersen G and Lindgren S.  “Involvement of the Entire Spinal Cord and Medulla Oblongata in Acute Catastrophic-Onset Transverse Myelitis in SLE.” Clin Rheumatol; 2000; 19; 156–160.

Rheu CW, Lee SI, and Yoo WH.  “A Catastrophic-Onset Longitudinal Myelitis Accompanied by Bilateral Internuclear Ophthalmoplegia in a Patient with Systemic Lupus Erythematosus.” J Korean Med Sci.  2005; 20: 1085-1088.

Strauss K, Hulstaert F, Deneys V, Mazzon AM, Hannet I, De Bruyk M, Reichert T, and Sindic CJM.  “The immune profile of multiple sclerosis: T-lymphocyte effects predominate over all other factors in cyclophosphamide-treated patients.” J Neuroimmunol. 1995; 63; 133- 142.

Takashima H, Smith DR, Fukaura H,  Khoury SJ, Hafler DA, and Weiner HL.  “Pulse Cyclophosphamide Plus Methylprednisolone Induces Myelin-Antigen-Specific IL-4-Secreting T Cells in Multiple Sclerosis Patients.” Clin Immunol and Immunopathology .  1998; 88; 28–34.

Allen_FinalAllen DeSena, MD, MPH | James T. Lubin Fellow | Department of Neurology, University of Texas at Southwestern, Dallas, TX