The(MCD), although adjuvant chemotherapy can be critical in severe cases, according to the first-ever consensus treatment guidelines based on symptom severity.
Early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe idiopathic MCD, according to the guidelines, which are based on input from 42 experts from 10 countries.
The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to guideline co-author, who is himself an idiopathic MCD patient. Frits van Rhee, MD, PhD, is the first author of the guidelines.*
“Right now we recommend siltuximab first line for everyone,” Dr. Fajgenbaum said in an interview, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”
Experts reviewed published literature and a series of 344 clinical cases to develop the guidelines, which are published in the journal.
Treating idiopathic MCD is challenging because of the rarity and heterogeneity of the disease, among other factors, said Dr. Fajgenbaum, of the division of translational medicine and human genetics at the University of Pennsylvania, Philadelphia.
Some 6,000-7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are idiopathic MCD, according to Dr. Fajgenbaum.
“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”
Although the exact etiology of idiopathic MCD is unknown, human interleukin (IL)-6 is the most common pathological driver, experts said in the guidelines.
Siltuximab and tocilizumab are two IL-6–directed therapies used to treat multicentric Castleman disease, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.
However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of idiopathic MCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.
“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.
Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.
Third line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.
Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe idiopathic MCD.
“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long term, but it can be life saving in the short term. So we recommended a really quite aggressive approach for these patients.”
To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up anto collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off label to treat idiopathic MCD, according to Dr. Fajgenbaum.
“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”
Dr. Fajgenbaum was diagnosed with idiopathic MCD as a medical student.
“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”
Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.
SOURCE: van Rhee F et al. Blood. 2018 Sep 4. .
This story was updated 10/01/2018.