IVIg and Rituximab-Based Regimens Are the Most Effective Treatments for CANOMAD Syndrome

Approximately one-third of patients with CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) syndrome have a hematologic malignancy, most commonly Waldenström macroglobulinemia (WM). Results from a retrospective study published in Blood suggest that B-cell targeted therapies such as intravenous immunoglobulin (IVIg) and rituximab-based regimens are the most effective treatments in patients with this rare disorder.

The study investigators, led by Marie Le Cann, MD, of the Pitié-Salpêtrière University Hospital in Paris, France, suggest these data support inclusion of CANOMAD in neurological monoclonal gammopathy of clinical significance (MGCS) and provide greater insight into the management of the disorder, which currently has no corresponding consensus regarding its treatment.

“CANOMAD syndrome is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular and/or bulbar motor weakness, in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes,” explained Dr. Le Cann. “Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce, and this study aims at collecting corresponding data.”

This French multicenter retrospective study enrolled 45 patients treated in 17 centers. All patients had at least 1 serum IgM antibody reacting against disialosyl epitopes in the context of neurologic symptoms. The investigators collected local information on monoclonal gammopathies, cold agglutinins, and anti-ganglioside antibodies using a standardized questionnaire that was sent to all referring clinicians.

Clinical features of CANOMAD were variable and could precede, be concurrent to, or appear during follow-up of a previously treated hematologic malignancy.

In this cohort, the median age at the onset of symptoms was 58 years, and the median delay between symptom onset and CANOMAD diagnosis was 4 years.

The primary clinical features of CANOMAD included:

  • sensory symptoms, including ataxia, paresthesia, hypoesthesia (100%)
  • motor weakness (40%)
  • ophthalmoplegia (45%)
  • bulbar symptoms (13%)

Cold agglutinins were identified in 34% of patients, and 45% of patients presented with moderate to severe disability, defined as a modified Rankin score of between 3 and 5. Clinical outcomes were mainly chronic progressive (67%) and relapsing-remitting (31%), the investigators noted.

All patients harbored a serum monoclonal IgM gammopathy (median peak value = 2.6 g/L; range = 0.1-40), and 16 patients (36%) had a diagnosis of an overt hematologic malignancy. The most frequent hematologic malignancy was WM, which was reported in 9 patients (20%). “Clinical characteristics of CANOMAD were largely similar between patients with or without an overt associated hematologic malignancy, notably in terms of ocular or bulbar involvement and degree of disability,” the authors reported, “and were not significantly associated with the level of IgM peak value.”

Most patients (91%) required treatment for CANOMAD, including 2 patients who received CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) chemotherapy for concomitant symptomatic hematologic malignancy. The remaining patients had minor symptoms or indolent disease course, except for 1 patient with acute respiratory distress who died due to pulmonary complications.

“Clinical features of CANOMAD can precede, be concurrent to, or appear during follow-up of a previously treated hematologic malignancy,” the authors wrote. “The clinical course was highly variable with some patients being wheelchair users after a few months despite therapeutic intervention and others remaining mobile after more than 10 years of follow-up without any treatment.”

Of those treated, patients received a median of 2 lines of therapy (range = 1-7). The overall clinical responses to first-line treatment was 44%, and responses were greatest in patients treated with IVIg or rituximab-based regimens, while treatment with corticosteroids and immunosuppressive agents was generally ineffective (TABLE). “In this regard, our data highlighted the benefit of targeting the B-cell clone in CANOMAD as it is already done in other types of MGCS,” said Dr. Le Cann. “As CANOMAD is frequently debilitating and treatments not codified, these data can help better therapeutic orientation for the patients, avoiding ineffective treatments.”

A limitation of this study included its retrospective design. Dr. Le Cann noted that the lack of data regarding delays in response to treatment also prevented the researchers from “drawing conclusions as to which treatment could be better suited to patients with rapidly progressive disease.” In addition, clinical evaluation was not centrally reviewed for these patients.

“These data plead for a more extensive entity that the acronym CANDA (chronic ataxic neuropathy with disialosyl antibodies) could better encompass,” concluded Dr. Le Cann.

The authors report no relevant conflicts of interest.

Reference

Le Cann M, Bouhour F, Viala K, et al. CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell targeted therapies. Blood. [Epub ahead of print]