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#ClinicSpeak: do you need a sledgehammer to crack a nut?

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Why high-dose cyclophosphamide is a not a treatment option for MS? #ClinicSpeak #MSBlog

Yesterday someone made the comment that cyclophosphamide, as part of the AHSCT (autologous hematopoietic stem cell transplant) conditioning and induction protocol, was the most effective treatment for MS. I disagree. Firstly, AHSCT does not use cyclophosphamide as monotherapy; most HSCT regimens include alemtuzumab, ATG (anti-thymocyte globulin) and other chemotherapy agents (e.g. BEAM - BiCNU/carmustine, Etoposide, Ara-C/cytarabine and Melphalan). Some newer protocols use follow-on rituximab as a maintenance treatment. Therefore you can't make the claim that cyclophosphamide is responsible for the efficacy of AHSCT.    

About 6 months ago one of my patients, a 34-year woman, with rapidly involving severe MS failed alemtuzumab therapy with a breakthrough spinal cord relapse at ~7 months post her second course of alemtuzumab. As we don't have funding in place in the NHS to give a 3rd course of alemtuzumab we had to consider other options. One of the options included HSCT (she was eligible under our the London AHSCT guidelines), however, when she was informed that the chances of her becoming infertile from the cyclophosphamide were over 40% she declined HSCT. That is the problem with cyclophosphamide; in high-doses it is seriously toxic to both the ovaries and testes and patients have to bank eggs (oocytes) and sperm. Cyclophosphamide is a potent immunosuppression so infections are a major risk. It also causes hair loss, mucositis, enteritis, hemorrhagic cystitis, nausea, vomiting, etc. I did my house job in a haemoncology ward and have personal experience with both allogeneic and autologous bone marrow transplantation and believe me we things go wrong they can go seriously wrong. Several of my patients died from the complications of bone marrow transplantation. I agree that things have improved markedly in the last 30 years, but there are still risks associated with HSCT that need to be carefully considered and this is why we are hoping to do a trial of AHSCT vs. alemtuzumab in the NHS to define the risk:benefit profile better. 

The high-dose cyclophosphamide proponents may be interested to hear that the John Hopkins group had a relatively large programme of high-dose cyclophosphamide as a treatment for highly-active MS. This treatment was called Revimmune. They have now stopped using Revimmune in MS because of the risks and because most of the patients had recurrence of disease activity about 18-24 months after the treatment. The latter is similar to our experience with mitoxantrone another chemotherapy agent used to treat highly active MS. So based on the above, and from the experience of the John Hopkins group, we would not recommend cyclophosphamide monotherapy to treat MS. We have also stopped using mitoxantrone for similar reasons and now offer off-label cladribine instead. 

So in an era of safer, more targeted, therapies why would anyone want to take the risks of their immune system and body being hit by a sledgehammer? These issues are likely to become major factors in how DMTs play out in the future; in particular the debate of continuous (fingolimod/natalizumab/ocrelizumab) vs. intermittent immunosuppression (alemtuzumab/cladribine/AHSCT) and non-selective (alemtuzumab/AHSCT) vs. selective immune reconstitution therapies (cladribine)

Dezern et al. Repeated treatment with high dose cyclophosphamide for severe autoimmune diseases. Am J Blood Res. 2013;3(1):84-90.

High dose cyclophosphamide (HiCY) without stem cell rescue has been shown to induce remissions in patients with severe autoimmune disorders (SADS). However, up to 80% of these patients ultimately relapse. Here we review the outcomes of seven patients treated with two cycles and one patient treated with three cycles of HiCY. The diseases re-treated were scleroderma, multiple sclerosis, three patients with severe aplastic anemia (SAA), and three patients with myasthenia gravis (MG). All but two patients with SAA had received standard immunomodulatory therapy for their disease up front and had been refractory. All patients had complete hematologic recovery. Overall survival in this cohort was 100%. All patients relapsed after the initial cycle but event free survival thereafter was 93.3%. All are still in remission except two MG patients, one of whom relapsed after a severe GI infection requiring hospitalization, and the other relapsed 3 years after the second treatment and she did not respond to the third treatment. This shows that HiCY can be safely re-administered in patients with SAA and refractory SADS. The quality and duration of second remissions appears to be equal or superior to the first remission.

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