Defining breakthrough disease: When to escalate

Abstract

An important subgroup of patients experience breakthrough disease on glatiramer acetate or IFNβ within 2 years of treatment initiation. One approach to managing patients with breakthrough disease is to switch them from one first-line therapy (e.g., glatiramer acetate) to another (e.g., an IFNβ formulation). However, there is no Class 1 evidence from randomized controlled trials examining the efficacy of switching from one FDA-approved monotherapy to another monotherapy in patients with ‘insufficient response’. This makes treatment decisions somewhat problematic. Furthermore, nonrandomized studies that have considered switches between IFNβ formulations and glatiramer acetate have not demonstrated consistent benefits for either approach A second potential approach to managing patients with breakthrough disease is to add an additional DMT to the patient׳s regimen (i.e., combination therapy). A number of randomized, controlled studies (providing Class 1 evidence) have been conducted to investigate the potential of add-on therapy Only add-on of monthly doses of oral methylprednisolone to IFNβ has demonstrated a beneficial effect on both relapse rate and MRI efficacy measures in both patients with breakthrough disease during treatment with IFNβ and de novo treated patients. Further trials are required to ensure that the benefit of these add-on therapies outweigh the potential risks of SAEs. A third approach to managing patients with breakthrough disease is to initiate treatment with a higher-efficacy monotherapy, such as natalizumab or mitoxantrone, although there is no Class 1 evidence from randomized controlled trials for either therapy in patients with breakthrough disease. While the pivotal trials for natalizumab were not designed to investigate this issue, recent data from a range of noncontrolled, observational studies (Class 4 evidence) have consistently indicated that natalizumab monotherapy is effective in patients with breakthrough disease. Additional studies are warranted. Some post-hoc analysis of phase III clinical trials have shown efficacy of fingolimod and dymethylfumarate in subgroup of patients with high disease activity, however the definitive used is questionable. ‘Real-world experience’ over the next few years will help to determine the usefulness of new agents, and it is hoped that future trials for patients with breakthrough disease will be conducted. Natalizumab will remain an important option in this setting, and the overall use of natalizumab may change after the JCV-assay proves an effective means to identify patients with higher risk of PML. It is currently more difficult to predict given the regulatory uncertainties for the oral agents .However, it seems reasonable to assume that a similar pattern will emerge over time.