A phase 2 prospective study of bortezomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed iMCD

TO THE EDITOR:

Human herpesvirus 8 (HHV-8)–negative idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder.¹ Patients with iMCD experience a wide spectrum of life-threatening cytokine storm–related symptoms including fatigue, fever, anorexia, weight loss, and ascites.² A subset of patients with iMCD have shared manifestations, including thrombocytopenia, anasarca/ascites, reticulin fibrosis in bone marrow, renal dysfunction, and organomegaly (TAFRO) and are identified as having the iMCD-TAFRO clinical subtype.³ Patients with iMCD not meeting the criteria for iMCD-TAFRO are considered to have iMCD-not otherwise specified (iMCD-NOS).

Interleukin-6 (IL-6) is known to play a key role in a portion of patients. Siltuximab, as an IL-6–directed monoclonal antibody, induced a complete or partial response rate of 34% in an international randomized controlled trial and showed a significantly improved progression-free survival (median, 14.5 months) compared with the placebo group.^4,5 However, real world data suggest that a significant portion of patients do not receive IL-6–targeted therapies, and treatment response does not occur in 50% to 60% of patients.⁶ Moreover, siltuximab is not available everywhere. Therefore, treatment regimens directed against targets other than IL-6 signaling should be further investigated. A combination of thalidomide, cyclophosphamide, and prednisone (TCP regimen) achieved an overall response of 48% at 24 weeks in patients with newly diagnosed iMCD.⁷ Subcutaneous bortezomib, along with oral cyclophosphamide and dexamethasone (BCD regimen), induced treatment responses in 62.5% of patients with refractory and relapsed iMCD by week 24. The safety profiles were well demonstrated in this study and a study of multiple myeloma.^8,9 

However, the efficacy and safety of this drug combination is unknown in patients with newly diagnosed iMCD. Herein, we performed a single center, open-labeled, single arm, phase 2 prospective pilot study to further illuminate the efficacy and safety profiles of the BCD regimen in patients with newly diagnosed iMCD. This study is registered in clinicaltrials.gov (NCT03982771). The study was performed in accordance with the Declaration of Helsinki, with prior approval of the institutional review board and the ethics committee of the local hospital. All enrolled patients provided signed informed consent.

A total of 30 patients newly diagnosed with iMCD at our hospital from June 2019 to September 2021 were enrolled in this study. All 30 patients were aged >18 years and met the consensus diagnostic criteria for iMCD.¹ Seven patients also presented with thrombocytopenia, anasarca/ascites, reticulin fibrosis in bone marrow, renal dysfunction, and organomegaly and were diagnosed as having the iMCD-TAFRO clinical subtype. All patients were previously untreated.

BCD regimen (subcutaneous bortezomib 1.3 mg/m² weekly, oral cyclophosphamide 300 mg/m² weekly, oral dexamethasone 40 mg weekly) was administered for 9 28-day cycles, followed by BD regimen (subcutaneous bortezomib 1.3 mg/m² every 2 weeks, dexamethasone 20 mg every 2 weeks) for 1 year. Treatment was discontinued after 1 year of maintenance or until treatment failure, which was defined as death or progression disease (PD). Acyclovir was prescribed as prophylactic antiviral therapy for herpes zoster reactivation. Supportive therapies were allowed, but other treatments targeting iMCD were prohibited.

The overall response rate at week 24 was 70%, with an overall complete remission (CR) rate of 10% and an overall partial remission (PR) rate of 60%. The symptomatic, biochemical, and lymph node remission rate at 24 weeks was 90%, 76%, and 70%, respectively (Figure 1). A total of 23 patients (77%) achieved overall treatment response of CR (13.3%) or PR (63.3%) after 9 cycles of BCD treatment, which lasted for ≥3 months. Although these subanalyses were limited by small sample sizes, the plasmacytic subtype (odds ratio [OR], 0.313; 95% confidence interval [CI], 0.032-3.068; P = .393), severe subtype (OR, 0.667; 95% CI, 0.130-3.414; P = .704), and iMCD-TAFRO clinical subtype (OR, 1.094; 95% CI, 0.169-7.061; P = 1.000) had similar overall response rates at week 24 compared with their counterparts. Six out of 7 (86%) patients with iMCD-TAFRO who received BCD regimens achieved an overall response by 24 weeks, with a CR rate of 29% and PR rate of 57%.

Significant improvements were seen in all 6 biochemical parameters at 24 weeks. The median levels of these parameters at baseline and week 24 are summarized in supplemental Table 2, available online at the Blood website. Among 4 patients with estimated glomerular filtration rate <30 mL/min per 1.73 m² at baseline, 2 patients had normalized estimated glomerular filtration rate by 24 weeks, 1 patient had postponed fully recovery of renal function at 18 months, and 1 patient was still on dialysis when followed up to 12 months.

The median follow-up time was 33 months (range, 3-41 months). A total of 10 patients experienced no response or PD and moved to the next treatment, and 2 deaths occurred. The follow-up time, time to next treatment (TTNT), and second-line treatments are listed in supplemental Table 3. The median TTNT was 36 months (range, 1-39 months), with no significant difference between nonsevere and severe groups (39 months vs 36 months, P = .917) or between iMCD-TAFRO and iMCD-NOS groups (not reached vs 36 months, P = .703). The 3-year OS was 93.3%, and there was no significant difference between the nonsevere and severe groups (88.9% vs 100%, P = .241) or between the iMCD-TAFRO and iMCD-NOS groups (85.7% vs 95.6%, P = .762) (Figure 2). The median OS time was not reached. No patients had adverse events of grade 2 or above. No patients died owing to treatment-related toxicity. Grade 1 peripheral sensory neuropathy (10%) was the most common adverse event, followed by grade 1 neutropenia (6.7%) and grade 1 nausea (6.7%). Adverse events are listed in supplemental Table 4.

To our knowledge, this is the first prospective trial enrolling patients with newly diagnosed iMCD that evaluated efficacy using the newly developed Castleman Disease Collaborative Network criteria. The BCD regimen attained an overall response of 70% at week 24, and 77% of patients achieved at least partial overall response after 9 months. Although direct comparisons cannot be made owing to potential confounders (eg, differences in inclusion criteria, response criteria, geographies) and differences in study design (eg, open label vs randomized controlled trial), the response rate appears to be similar to or higher than in newly diagnosed iMCD treated with TCP regimen, which achieved a durable tumor and symptomatic response in 48% of patients, or in symptomatic iMCD (previously treated or newly diagnosed) treated with siltuximab, which achieved a durable tumor and symptomatic response in 34% of patients.^4,7 Considering the fact that IL-6–targeted treatment is not readily available everywhere and not effective for every patient and that BCD regimen seems to be safe, effective, and more widely available, BCD regimen is a promising treatment option for patients with newly diagnosed iMCD who cannot access IL-6–directed therapies.

This study was also the first prospective trial, to our knowledge, to describe the treatment response of patients with iMCD-TAFRO to a preassigned regimen. Patients with iMCD-TAFRO treated with BCD regimen had a similar response rate and similar TTNT and overall survival compared with patients with iMCD-NOS. This result supports this combination therapy to be used for patients with iMCD-TAFRO, as it may be able to overcome the poor prognosis of iMCD-TAFRO. The high response rate achieved with BCD regimen in iMCD-TAFRO might be attributed to the rapid onset of the effect of bortezomib and antiinflammatory effect of high-dose dexamethasone, which could alleviate the cytokine storm accompanied by iMCD-TAFRO.¹⁰ 

The BCD regimen in our study was maintained only for 21 months, and we observed PD in some patients after BD regimen withdrawal, suggesting that it is necessary to identify patients who will need long-term maintenance treatment in the future.¹¹ 

In conclusion, BCD regimen is an effective and safe treatment option for patients with newly diagnosed iMCD, especially in patients with severe iMCD and patients with iMCD-TAFRO who cannot access anti-IL–6 therapy.