Remission of severe myasthenia gravis after autologous stem cell transplantation

Abstract

Objective: Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular junction disorder involving the acetylcholine receptors on the motor endplate. The safety and response to high-dose chemotherapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were assessed in a patient with severe refractory MG.

Methods: As part of a pilot study of HDIT/HCT for patients with treatment-resistant autoimmune neurological disorders, a patient with severe refractory MG underwent treatment. After mobilization of hematopoietic stem cells with rituximab, prednisone, and G-CSF, the patient had HDIT consisting of carmustine, etoposide, cytarabine, melphalan, and rabbit antithymocyte globulin, followed by autologous HCT. The effect of treatment on the autoantibody to the acetylcholine receptor (AChR) was assessed.

Results: The patient had been diagnosed with AChR antibody-positive MG 14 years before HDIT/HCT and had failed thymectomy, therapeutic plasma exchange, and multiple immunomodulatory agents. The Myasthenia Gravis Foundation of America (MGFA) clinical classification was IVb before HDIT/HCT. She tolerated HDIT/HCT well and started to improve clinically within days of treatment. At both 1 and 2 years after HDIT/HCT, patients remained symptom-free. After HDIT/HCT, AChR-binding autoantibodies persisted, and the relative frequency of immune cell subtypes shifted.

Interpretation: HDIT/HCT induced a complete response of disease activity in a patient with severe refractory MG. This response may suggest that a cell-mediated etiology may be a significant contributing factor in refractory MG cases. A phase 2 clinical trial is warranted to establish if HDIT/HCT can be an effective therapy for severe refractory MG and to gain a further understanding of disease pathogenesis.

Figure 1

Acetylcholine receptor (AChR)‐binding autoantibodies persist post‐hematopoietic cell transplantation (HCT), though autoantibody‐mediated complement activity diminishes. Live CBA using transiently AChR‐transfected HEK293T of (A) serum and (B) isolated Ig to detect the presence of AChR autoantibodies in three pre‐HCT and two post‐HCT serum samples. (C) Representative flow cytometry plots depict MAC formation, indicative of AChR autoantibody‐mediated complement activity, upon incubation of pre‐HCT serum with AChR‐expressing cells in a modified CBA. (D) AChR autoantibody‐mediated complement activity measured in pre‐HCT and post‐HCT samples, HD, and an AChR‐positive MG patient serum known to mediate autoantibody‐mediated complement activity. The dotted line represents background (NHS only) complement activity. Each point represents the mean of triplicate experimental conditions. Extended results for the assay data are shown in Table S2.

Figure 2

Skewed natural killer (NK) cell subset frequency is normalized following hematopoietic cell transplantation (HCT). Reduced cytotoxic NK cell frequency was observed prior to HCT and returned to HD levels post‐HCT. (A) Representative flow cytometry plots depict NK cell subsets based on CD16 and CD56 expression. (B) Frequencies of NK cell subsets as a percentage of the parent population are shown. NK cells are gated as CD56⁺CD3⁻CD14⁻CD19⁻ from the singlet lymphocyte population; the remaining NK cell subsets are displayed as the frequency of the NK cell gate. Each dot for pre‐ and post‐HCT represents a different time point (n = 2), and each dot for HD represents an individual donor (n = 4); bars show the mean and SEM.