Due to the rarity of iMCD, data regarding treatment is limited and based on a combination of observational case series, case reports, and a single randomized clinical trial. Unlike UCD, for which surgery is the treatment of choice and curative for most patients, surgery is not effective in iMCD. Instead of surgical treatment, a variety of medications are used based on disease severity and a patient's response to prior treatments. Siltuximab, a monoclonal antibody targeting IL-6, is the only medication approved by the United States Food and Drug Administration (FDA) for the treatment of iMCD; however, successful use of other medications has been reported in the literature. In 2018, the first evidence-based consensus treatment guidelines for iMCD were published by an international group of experts in the field. In addition to creating a treatment algorithm for iMCD, these treatment guidelines established common definitions for disease severity and response to treatment. Evaluation of iMCD Severity Patients with iMCD are classified as having severe or non-severe disease based on the 5 criteria listed below. Patient with 2 or more of the below criteria are classified as having severe disease while patients with 0-1 of the criteria are classified as having non-severe disease. * Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2 * Estimated glomerular filtration rate (eGFR) 3.0 mg/dL * Anasarca and/or ascites and/or pleural effusion and/or pericardial effusion * Hemoglobin ≤ 8.0 g/dL * Pulmonary involvement (e.g. interstitial pneumonitis with dyspnea) Treatment response Patients with iMCD are evaluated for treatment response based on changes in symptoms, sizes of involved lymph nodes, and laboratory testing. Each category is graded as a complete response, partial response, stable disease, or progressive disease. Overall treatment response is determined by the lowest category grade. For example, a patient with a complete laboratory response, a partial symptom response, and complete lymph node response would be given an overall treatment response of partial response. See below for descriptions of the criteria and grading of responses. Laboratory Testing Laboratory tests include all of the following: C-reactive protein, Hemoglobin, Albumin, and eGFR. * Complete response - All lab values within normal ranges * Partial response - >50% in all lab values * Stable disease - All lab values between 25% worsening in any lab value Symptoms Four symptoms are assessed using the National Cancer Institute Common Terminology Criteria of Adverse Events (version 4): Fatigue, anorexia, fever, and body weight * Complete response - Normalization to pre-disease baseline * Partial response - Improvement in all 4 symptoms, but not to pre-disease baseline * Stable disease - Improvement in at least 1 (but not all) symptoms * Progressive disease - Worsening of at least 1 symptom on 2 or more assessments Lymph Node Treatment response for lymph nodes is evaluated using radiologic imaging and graded as complete response, partial response, stable disease, and progressive disease based on modified Cheson criteria. Treatment Algorithm The treatment algorithm for iMCD is based primarily on disease severity and response to treatment. Because of the high rate of relapse with withdrawal of treatment, most patients with iMCD are treated with medications indefinitely. Non-severe disease Siltuximab, an IL-6 blocker, is the recommended treatment for all patients with non-severe iMCD regardless of measured IL-6 levels. Tocilizumab, a drug that also targets the IL-6 pathway, is commonly used as an alternative to siltuximab when siltuximab is unavailable. Corticosteroids may be added to anti-IL-6 therapy depending on clinical presentation. Rituximab, a drug targeting B-cells, is primarily recommended as a second line therapy for patients who do not respond to siltuximab or tocilizumab, but may be used as a first line agent in appropriate patients. For patients with non-severe disease who fail to respond to siltuximab, tocilizumab, and rituximab, treatment recommendations are not well defined. Cytotoxic chemotherapies have been reported to induce remission in patients with non-severe iMCD; however, the use of cytotoxic chemotherapies is not currently recommended for non-severe iMCD due to high likelihood of relapse and severe side effect profiles. As an alternative, immunomodulators such as thalidomide, cyclosporine A, sirolimus, bortezomib, and anakinra are recommended due to their similar response rates and more favorable long term side effect profiles. Severe disease Recommended initial treatment for all patients with severe iMCD is high dose steroids combined with an anti-IL-6 agent such as siltuximab or tocilizumab, regardless of measured IL-6 levels. For patients who immediately improve with this regimen, steroids may be slowly tapered, but the anti-IL-6 agent should be continued indefinitely due to the high relapse rate with withdrawal of treatment. Due to the high risk of complications associated with severe iMCD, if patients worsen or fail to improve with high dose steroids and anti-IL-6 therapies, cytotoxic chemotherapy regimens are recommended. Patients with life-threatening disease, particularly those with TAFRO Syndrome, may require advanced measures such as breathing support with a mechanical ventilator or treatment with dialysis for kidney failure. Following improvement in disease status, maintenance therapy with an anti-IL-6 agent or an immunosuppressant medication is typically continued indefinitely, as withdrawal of such medications can lead to relapse. Follow-up Patients with iMCD require routine assessment of treatment response and disease progression. It is recommended that follow-up visits include evaluation of symptoms, physical examination, laboratory testing, and radiologic imaging.
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Unicentric Castleman disease
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