Alemtuzumab: the future of chronic inflammatory demyelinating polyradiculoneuropathy treatment?

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), an autoimmune neuropathy, is one of the most commonly encountered treatable neuropathies [1]. It accounts for approximately 20% of initially undiagnosed neuropathies [2,3]. At some point during the course of the disease, 54% of patients are disabled [4]. Intravenous immune globulin (IVIg), plasmapheresis and prednisolone have all been studied in randomized placebo-controlled trials and are considered to be first-line treatments [5]. Not all patients respond to these treatments [6], and in some the response is suboptimal or there are significant side effects. In addition, the majority of patients require ongoing treatment; therefore, there is concern about the high cost of IVIg and plasmapheresis, the serious side effects associated with chronic corticosteroid use and the high cost of these side effects [5,7–9].

Owing to the drawbacks of current treatments, there is an ongoing search for a safe treatment that will result in a cure or long-lasting remission for patients with CIDP. A report of a single patient with CIDP who was treated with alemtuzumab and had a long-lasting remission has led to this drug gaining attention as a potentially promising treatment [10].

There have been other attempts at inducing a cure or long-term remission in patients with CIDP. Lymphoid irradiation was used in four patients with CIDP and three had remissions, with follow-up for 12 months. Six patients have been described who recieved autologous stem-cell transplants for CIDP. Four out of these six experienced negative outcomes and either did not respond at all or initially showed improvement before relapsing later. The remaining two patients were reported to be in remission with follow-up of 6 months and 22 months [11–15]. One patient, treated with allogeneic bone marrow transplantation, experienced a remission with follow-up for 6.5 years [16]. High-dose cyclophosphamide (200 mg/kg) without stem-cell rescue was initially used in four patients with CIDP and resulted in long-term remission in all four [17]. Expanding upon this, ten patients in total were treated and with longer follow-up, resulting in long-term remission in just over half of the patients [18].

Alemtuzumab is a recombinant, humanized monoclonal antibody (IgG1k) that targets the CD52 antigen. It is US FDA-approved for the treatment of B-cell chronic lymphocytic leukemia. CD52 is ubiquitously expressed on most B and T lymphocytes, as well as on macrophages and monocytes, with little expression on hematologic stem cells. The function of CD52 is unknown, although it may be involved in T-cell migration and costimulation [19]. After binding to the CD52 antigen, alemtuzumab causes cell death via antibody-dependent cellular cytotoxicity and apoptosis [19,20]. Alemtuzumab causes a depletion of CD4⁺ cells for a median of 61 months, CD8⁺ cells for 30 months and B cells for a shorter period, with levels rising above baseline at 27 months [21]. Although the pathogenesis of CIDP is not completely understood, current data support the involvement of both cell-mediated and humoral immunity along with an initial loss of self-tolerance. Activated T cells are seen in nerves, having crossed the blood–nerve barrier, and may be important to disrupt the blood–nerve barrier and allow the passage of antibodies and macrophages. Macrophages can attack intact myelin and are the major endoneurial cell in CIDP. Antibodies and complement deposits are seen in nerve biopsies and antibodies are suggested to lead macrophages to myelin and activate complement [1,22]. Thus, alemtuzumab, which affects multiple arms of the immune system, is an attractive agent for use in CIDP.

The initial patient, a 19-year-old woman with relapsing and remitting CIDP, initially improved with IVIg and had no benefit with prednisone treatment. After receiving alemtuzumab, she had two additional relapses in the first 8.5 weeks, but then showed sustained improvement and was able to stop all immunomodulatory medications. Her remission lasted for 9 months, at which time she relapsed again and was again given alemtuzumab. She experienced no adverse effects [10,23].

Since the initial report of their patient who experienced long-term remission after treatment with alemtuzumab, the authors have provided further follow-up information, as well as a description of six other patients whose data were collected retrospectively from those treated in the UK and Ireland [23]. Among this group, patients had previously been treated with prednisolone, IVIg, azathioprine, cyclophosphamide, rituximab, plasma exchange, tacrolimus, methotrexate and mycophenolate, and one had received an autologous stem-cell transplantation. They included patients for whom IVIg every 2–5 weeks was necessary to maintain function. Also recorded were the total monthly IVIg dose and the frequency of treatment with IVIg in the 12 months preceding and following treatment with alemtuzumab. The originally described patient had a 9-month remission followed by retreatment with alemtuzumab. After the second course, she had four relapses in the first 9 weeks and then a remission lasting for 17 months. She then relapsed again and has since required IVIg every 6 weeks. She declined further alemtuzumab. Long-term remission was seen in one additional patient, a 17-year-old man, with CIDP for 3.5 years prior to treatment, with follow-up of 31 months. Out of the remaining five patients from the seven mentioned, two patients had a partial response and three received no benefit from the treatment.

A disconcertingly high proportion of these patients developed autoimmune thyroid and hematologic problems, which were possibly related to treatment with alemtuzumab. Of the seven patients, two developed high levels of anti-thyroperoxidase antibodies and one of these two patients developed thyroid-stimulating hormone receptor antibodies and Grave’s disease [23]. Another patient developed autoimmune hemolytic anemia, had a splenectomy and then arrested following a decline in his hemoglobin. At post-mortem, the cause of death was not identified [23].

Previous clinical trials with multiple sclerosis patients have demonstrated a beneficial effect with alemtuzumab; however, frequent autoimmune disease occurred. In total, 27% developed autoimmune thyroid disease and 3% of patients also developed immune thrombocytic purpura. These autoimmune diseases may be driven by elevated IL-21 levels. A pretreatment IL-21 level greater than 210 pg/ml has 66% sensitivity and 67% specificity to predict the development of autoimmune disease after the use of alemtuzumab [20]. These autoimmune diseases have not occurred in patients with cancer, and are only seen in patients treated for autoimmune disease, such as multiple sclerosis, vasculitis and CIDP [20,23–25].

Serious infections have occurred in patients treated for lymphoproliferative diseases and following transplantation, including progressive multifocal leukoencephalopathy and aspergillus [26,27]. Serious infections have not been common in patients treated for multiple sclerosis [25]. No infections were reported in the patients treated for CIDP [10,23].

At this time, there are very limited data to make a judgment regarding the potential role of alemtuzumab in CIDP. Only two out of seven patients had prolonged remissions and one of these patients then required retreatment. Also interesting and potentially significant is that both of the patients who had long-term remissions were in their teens. CIDP is a heterogeneous disease and this age group more frequently has a relapsing and remitting course [28], which may have influenced the positive response in these cases.

The frequently occurring autoimmune hematologic and thyroid diseases make the use of this medication concerning. If high levels of IL-21 secretion, which is genetically determined, do indeed play a role in the development of the autoimmune complications and can be measured prior to the administration of alemtuzumab, then it may be possible to identify appropriate candidates for treatment. However, at this time, it remains unclear whether alemtuzumab will play a role in the future as a treatment for patients with CIDP. A much better understanding of both the medication’s efficacy and the associated risks is first required.

Financial & competing interests disclosure

Thomas H Brannagan has served as a consultant and received honoraria from Talecris. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.