Continuous therapy in HHV-8 negative Multicentric Castleman Disease and prolonged progression-free survival

Abstract

The optimal treatment endpoints and duration of continuous therapy for multicentric Castleman disease (MCD) remain controversial. We retrospectively analyzed data from 123 patients with Human Herpesvirus (HHV)-8 negative MCD. We demonstrated that continuous therapy significantly enhanced progression-free survival (PFS) in patients who achieved an optimal response after initial treatment. These findings underscore the critical role of continuous therapy in HHV-8 negative MCD. Further studies with larger cohorts are required to validate these findings.

To the editor:

Multicentric Castleman disease (MCD) is a heterogeneous group of rare, systemic, progressive, and fatal diseases with lymphadenopathy in multiple nodes [1, 2]. An international consensus published in 2018 recommended anti-IL-6-based therapy as the first-line treatment for all patients with idiopathic MCD (iMCD) [3]. Zhang et al. also described a national trend of treatment options in China, with a shift from pulse chemotherapy to continuous approaches [4]. However, there is an ongoing debate about the “when to stop” issue: whether we should treat MCD with the goal of achieving a complete response (CR) and, once the desired response is achieved, whether the continuous therapy is still necessary [5,6,7,8,9]. This retrospective study aimed to evaluate the role and impact of continuous therapy in HHV-8 negative MCD.

A total of 123 patients diagnosed with HHV-8 negative MCD at the First Affiliated Hospital of Zhejiang University from 2015 to 2023 were identified, including 8 POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, and skin changes)-associated MCD (Figure S1). Patients had poor overall condition, with 67.5% (83/123) evaluated with an Eastern Cooperative Oncology Group (ECOG) score ≥ 2 and 46.3% (57/123) classified with severe disease [10]. Patient baseline characteristics are summarized in Table 1 and Figure S2A. We categorized the regimens according to the year and first-line options (Figure S2 and Supplementary Data1). Between 2015 and 2019, R-CHOP or R-CHOP-like therapy (14.3%, 6/42), and CHOP or CHOP-like therapy (23.8%, 10/42) were the most common regimen options. Since 2020, continuous treatment approaches have gradually become the first choice, utilizing IL-6 targeted therapy (17.9%, 14/78) and RVD/RCD/RD (30.8%, 24/78).

Table 1 The clinical and laboratory characteristics of HHV-8 negative MCD patients

After a median follow-up of 22.7 months, the median overall survival (OS) [95% CI, Not Reached (NR) to NR] and PFS (95% CI, NR to NR) of all patients were not reached (Fig. 1A-B). Univariate and multivariate Cox regression analyses were performed to identify risk factors (Table S1-S2). Stratified by severity, patients with severe MCD had significantly worse OS (p = 0.03) and PFS (p = 0.01) than those in the mild MCD group (Figure S3A-B). Compared to patients without systemic symptoms, those experiencing a flare had worse OS (p = 0.006), although the difference in PFS (p = 0.41) was not statistically significant (Figure S3C-D). Subsequently, we stratified the patients with MCD based on different treatment endpoints. As shown in Fig. 1C-D, patients achieving the best response to CR, partial response (PR), or stable disease (SD) exhibited significantly longer OS than those who only progressed to progressive disease (PD) (p = 0.0001). However, neither obtaining CR nor PR significantly extended both OS or PFS compared to patients with SD.

To assess the impact of sustained treatment on the prognosis of patients who achieved an optimal response after initial therapy, we designated patients who achieved PR or CR after 4–6 cycles of initial treatment as study participants. Patients who continued treatment for at least 3 months were classified into the continuous treatment (CT) group, while others were classified into the non-continuous treatment (NCT) group. Among the 54 patients who achieved their best response, 22 and 32 were classified into the CT and NCT groups, respectively. There were no significant differences in baseline characteristics (Tables S3). By the end of the follow-up period, 10 patients were still undergoing continuous treatment, 9 patients had ceased treatment and continued regular follow-up, 2 patients had relapsed, and 1 patient died from disease relapse following autologous hematopoietic stem cell transplantation (ASCT). Dynamic responses and continuous therapy options are presented in Fig. 1E. As depicted in Fig. 1F, continuous therapies were classified as rituximab-based therapy, thalidomide-based therapy, bortezomib-based therapy, immunomodulators, or glucocorticoids. Patients receiving continuous therapy had significantly improved PFS compared with those who did not receive maintenance therapy (p = 0.048) (Fig. 1H). However, the OS was not significantly different between the two groups (p = 0.058) (Fig. 1G).

In summary, although there are unavoidable challenges of potential bias, particularly in the context of such a rare disease, the significant improvement in PFS observed in the CT group reinforces the importance of continuous therapy as a crucial intervention for patients with HHV-8 negative MCD who have achieved an optimal response. However, the rarity of the disease and the heterogeneity of treatment approaches necessitate further research with larger cohorts and extended follow-up periods to validate our findings.

Fig. 1

(A) Overall Survival analysis of all MCD patients. (B) Progression Free Survival analysis of all MCD patients. (C) Subgroup Overall Survival analysis of MCD patients based on best treatment response. (D) Subgroup Progression Free Survival analysis of MCD patients based on best treatment response. (E) The Swimmer’s plot shows the dynamic responses and different continuous therapies of MCD patients. The horizontal axis represents the duration of continuous therapy after patients achieved their best response. (F) Sankey plot illustrates the progression from the initial treatment regimen to the best response, and subsequently, to various continuous treatment options. (G) Subgroup Analysis of Overall Survival by Continuous Therapy. (H) Subgroup Analysis of Progression-Free Survival by Continuous Therapy

Abbreviations: MCD (multicentric Castleman disease); CR (Complete Response); PR (Partial Response); SD (stable disease); PD (progressive disease); BCD (bortezomib, cyclophosphamide, and dexamethasone); BD (bortezomib, and dexamethasone); CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); HV (hyaline vascular); RCD (rituximab, cyclophosphamide, dexamethasone); RD (rituximab, dexamethasone); R-CHOP/R plus glucocorticoids (R, rituximab); RVD (rituximab, bortezomib, dexamethasone); CT (Continuous Therapy);