Evaluating Thalidomide-Cyclophosphamide-Prednisone for Idiopathic Multicentric Castleman Disease

An oral combination of thalidomide, cyclophosphamide, and prednisone (TCP) induced durable tumor and symptomatic response rates in nearly half of patients with newly diagnosed idiopathic multicentric Castleman disease (iMCD), according to a small phase II study published in Blood. The researchers also found that the TCP regimen was relatively safe, with no patients experiencing grade ≥3 adverse events (AEs).

“Although the anti-IL6 therapy siltuximab has been recommended as firstline therapy for all patients with iMCD – according to the first-ever expert consensus [for iMCD treatment] – this drug is not effective for more than half of patients and is not available everywhere,” said co-author Jian Li, MD, from the Peking Union Medical College Hospital in Beijing. Its high price and the requirement for repeated intravenous administration also limit its use as firstline therapy in lower-income countries.

In this single-center trial, Chinese researchers evaluated the safety and efficacy of TCP as an alternative treatment for patients with newly diagnosed iMCD who do not respond to or do not have access to siltuximab.

A total of 25 patients (median age = 40 years; range not reported) were enrolled between June 2015 and June 2018. All participants had histopathologic lymph node features consistent with iMCD.

Treatment with TCP also was associated with significant improvements in symptom score, IL-6 level, hemoglobin, erythrocyte sedimentation rate, albumin, and immunoglobin G.

TCP was administered for two years or until treatment failure in the following treatment schedule:

  • thalidomide 100 mg/day at bedtime for years 1-2
  • cyclophosphamide 300 mg/m2 weekly on days 1, 8, 15, and 22 of a 4-week cycle for year 1
  • prednisone 1 mg/kg on days 1-2, 8-9, 15-16, and 22-23 of a 4-week cycle for year 1

The primary endpoint was the incidence of durable tumor and symptomatic response sustained for at least 24 weeks. Responses were defined as:

  • complete response (CR), or complete disappearance of measurable and evaluable disease as well as a resolution of iMCD-associated baseline symptoms
  • partial response, or ≥50% reduction in the sum of the product of diameters of measurable lesions, with at least stable disease in the absence of treatment failure (defined as sustained increase in disease-related symptoms, initiating a new iMCD treatment, or death)

After administration of TCP, 12 patients (48%) met the primary endpoint for response, seven of whom had achieved CR. Three patients (12%) had stable disease, and the remaining 10 patients (40%) experienced treatment failure. The authors observed that responders were more likely to have fever (p=0.008) and less likely to have pulmonary involvement (p=0.039) at baseline, compared with nonresponders.

Treatment with TCP also was associated with significant improvements in symptom score, IL-6 level, hemoglobin, erythrocyte sedimentation rate, albumin, and immunoglobin G from baseline (all p<0.05; TABLE).

During follow-up, one patient died from pulmonary infection and one patient had a grade 3 AE; another patient died from disease progression. The most common grade 1-2 AEs included: constipation (40%), pruritus (20%), rash (16%), peripheral sensory neuropathy (16%), and nausea (16%).

During the median follow-up of 14 months (range = 6-36 months), estimated progression-free and overall survival rates were 60 percent and 88 percent, respectively. However, the actual survival data were not reported, which limits the applicability of these findings.

“As a single-arm study without a control group, it is difficult to perform a rigorous comparison between the TCP regimen and other treatment options, and further study is needed,” Dr. Li explained. “However, according to our clinical experience with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like regimens – which were the most widely used therapies for Chinese patients when siltuximab was unavailable – oral TCP represented an economical and convenient treatment option with good safety profiles and acceptable response rates.”

Dr. Li noted that investigators are continuing to collect data on the long-term efficacy and safety of this regimen. “Moreover, a well-designed multicenter trial that employs the new consensus response criteria is needed,” he added. “Hopefully, a controlled study with siltuximab will be carried out in the future.”

The authors report relationships with Janssen Pharmaceuticals.

Reference

Zhang L, Zhao AL, Duan MH, et al. Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic Multicentric Castleman disease. Blood. 2019 February 13. [Epub ahead of print]

SHARE