Siltuximab for MCD

Corey Casper, MD, MPH:Currently, the only FDA-approved treatment for Castleman’s disease is a drug known as siltuximab. Siltuximab is an inhibitor of interleukin-6 which is thought to be central to the pathogenesis of idiopathic and even all forms of Castleman’s disease. So, siltuximab works by essentially, scavenging soluble interleukin-6 and inhibiting its binding to the IL-6 receptor. That activity is incredibly specific for interleukin-6 and has been shown to have very dramatic effects on Castleman’s disease. Really, right now, it’s the only FDA-approved treatment for Castleman’s disease and is widely becoming, I would say, the most common first-line therapy for the disease.

The FDA-approved indication is for the use of siltuximab in idiopathic multicentric Castleman’s disease. There are a couple of important pieces of that. Idiopathic meaning not related to herpesvirus-8 and multicentric meaning disease that is not just involving single lymph node or lymph node chain. In the FDA indication for this drug, it’s important to consider that its utility and the way it’s been tested has been in this setting. The licensure study that was conducted was a randomized placebo-controlled trial which is really important for a disease that has such diverse manifestations. Patients were randomized in a 2:1 fashion to drug or to placebo. They could enroll on the study if they had idiopathic multicentric Castleman’s disease. I would say that the study selected for patients with moderate disease. If they were asymptomatic, they couldn’t be included. You had to have symptomatic disease, but if the patients were too sick, for instance, if they had multi-organ system failure, they also couldn’t be enrolled in the study.

The study enrolled patients with moderate idiopathic multicentric Castleman’s disease and no other active infections that could be measured, so viral hepatitis or HIV were excluded. And, these patients received either the drug or placebo over the course of several years. The patients were allowed to cross over, so patients receiving placebo could cross over to receiving the active drug if their providers felt as if they had no benefit after at least 18 weeks of receiving therapy. The study was designed to look at discrete endpoints, reduction in the size of key lymph nodes using the RECIST criteria, but also other associated biochemical abnormalities. So, changes in anemia and changes in inflammatory biomarkers were secondary endpoints. The study also collected patient-reported outcomes, although FDA doesn’t typically allow those to be used for indications for licensure. Those were collected and recorded as secondary endpoints but not primary endpoints.

The study was quite remarkable in the sense that for those main primary endpoints, 0% of patients in the placebo arm met the criteria for radiographic improvement. I should also mention that the criteria for radiographic improvement were quite strict, so patients had to see a reduction in the size of their sentinel lymph nodes by at least 25%. And so, those were the patients that were deemed to have responded to the drug in the study. Many patients in the study actually felt better and had improvements in their laboratory abnormalities, but if they didn’t meet that primary endpoint of improvement of at least 25% in their lymph nodes, they were not considered as being treatment successes. But, meeting those strict criteria, close to 50% of patients had a response to siltuximab and 0% of the patients receiving placebo had a response.

Furthermore, the drug was incredibly well tolerated. There were a number of grade 1 and 2 toxicities seen with the drug. There were few grade 3 and grade 4 toxicities, but notably, they were the same in patients receiving placebo and patients receiving siltuximab. And, what that tells me is that for patients with Castleman’s disease, they may have a lot of associated symptoms that get cored as toxicity of the drug, but because they happened as frequently on placebo as they did on the drug arm, we can’t attribute those to the drug but to the underlying disease. We know that the drug was effective, it was safe, and patients also tolerated the drug for long periods of time. So, in other studies of siltuximab, either the open-label or phase I portions, it was reported that the long-term safety of the drug is excellent.

For siltuximab, again, it’s indicated for idiopathic, symptomatic, multicentric Castleman’s disease without other chronic infections and we saw incredible response rates to the drug, but very little toxicity that could be specifically attributable to the drug and few long-term toxicities. And, for the multicentric disease, I make a branch point at my decision making between human herpesvirus-8—associated and idiopathic disease. For the human herpesvirus-8 disease, my first line of therapy is antiviral therapy. Whereas, for patients with idiopathic multicentric Castleman’s disease, if they have no other contraindications to the use of an interleukin-6 inhibitor, I start with siltuximab in those patients.

Unfortunately, not all patients respond to first-line therapy, or even those that do respond may find themselves progressing or relapsing. For patients who are initially treated with siltuximab, generally that treatment is lifelong. We’ve found that the treatment is durable and I’ve seen very few patients who progress while on siltuximab. But, for those patients who do progress on siltuximab or for those who stop the drug and relapse, there are different approaches. When topping the drug leads to relapse, in my experience, restarting the drug is sufficient to regain control over the disease. So, prior receipt of the drug doesn’t seem to confer subsequent resistance to it. However, for those that progress on the drug or don’t respond as completely as you would like, in my mind, the next option for therapy would be either rituximab to more broadly destroy the CD20 molecule or the other option in those patients would be conventional chemotherapy. And, in my mind, I think about the different histologic variants. A hyaline vascular variant, to me, behaves more like a lymphoma and we treat with lymphoma-like regimens, CHOP or CVP. And the plasma cell variant behaves more like a myeloma because of the predominance of plasma cells and tends to respond to regimens like lenalidomide and dexamethasone.

For relapsed or refractory disease, that’s my approach. I would say, too, that oftentimes we get referred patients who have not received siltuximab as first-line therapy. They’ve received conventional chemotherapy or they’ve received rituximab. And, we now have pretty good data from the licensure study that even those patients who are not treatment-naïve, so patients who have previously received therapy with siltuximab or conventional chemotherapy, they, too, enjoy the same response rates to siltuximab. Prior receipt of chemotherapy or biologic therapy does not influence the subsequent response rates in that setting of relapse or refractoriness to siltuximab.

Corey Casper, MD, provides information on the diagnosis and treatment of patients with Castleman Disease (CD).