Changes in the clinical features, treatments, and outcomes of patients with systemic light chain (AL) amyloidosis in Western China, 2010–2022: A multicenter, retrospective, real-world study

To the Editor: Systemic light chain (AL) amyloidosis, a rare and deadly disease affecting approximately 10 individuals per million each year worldwide, is marked by misfolded, aggregated immunoglobulin light chains produced by dangerous plasma cell or B cell clones. Diagnosis of AL amyloidosis often faces obstacles due to non-specific symptoms. Owing to a deeper understanding and therapeutic advancements of AL amyloidosis, patients’ overall survival (OS) has significantly improved globally.[1,2] However, data of China’s situation remain limited, especially since the novel therapeutic agents were included in the national medical insurance reimbursement list (NMIRL) in late 2017, systemic light chain is listed in the first national list of rare diseases released, and the neoplasm multidisciplinary teams (MDTs) was established by the National Health Commission of China in 2018. Therefore, a multicenter, retrospective, real-world study (AMY4002) was conducted in Western China to report the clinical baselines, treatment patterns, and outcomes of Chinese AL amyloidosis patients before and after 2018. Patients’ demographics, clinical characteristics, treatment choices, hematological response, organ response, and OS were collected. In patients undergoing upfront autologous stem cell transplantation (ASCT), the date of receiving ASCT was considered the treatment initiation date. Patients subjected to induction chemotherapy followed by ASCT were not classified as receiving second-line therapy, but rather were classified as having undergone consolidative ASCT. The overall response rate (ORR) was defined as the proportion of patients achieving a partial or better hematologic response, excluding patients with missing data on response assessment. OS was defined as the time from treatment initiation to either death from any cause or the last follow-up. Cases lost to follow-up were treated as censored data and included in the analysis. Flowchart of this study is showed in [Supplementary Figure 1, https://links.lww.com/CM9/C143], and detailed methods are presented in the Supplementary Files, https://links.lww.com/CM9/C143. Each participating center’s Institutional Review Board and the Human Genetic Resource Administration of China approved the study (2021GH4444 and 2021CJ1335). The study, registered with the Chinese Clinical Trial Registry (ChiCTR2100054499), was conducted following the Declaration of Helsinki. All patients provided informed consent. Overall, 505 patients with confirmed pathological diagnoses were enrolled. The positive rate of amyloid deposits in the bone marrow (27.4%, 48/175) in confirmed patients was lower than that in Western countries (50–60%).[3] The demographic and clinical features at diagnosis are outlined in Supplementary Table 1, https://links.lww.com/CM9/C143. The organs most commonly affected were the heart (72.5%, 366/505) and kidneys (67.7%, 342/505), with multiorgan involvement in 72.5% (366/505) of patients. Although earlier Chinese reports emphasized a high renal involvement rate, our data indicated that cardiac and renal involvement rates were similar to those reported in Western studies.[1,2] This discrepancy may be due to the increased diagnosis of renal amyloidosis resulting from the more frequent use of kidney biopsies. Only 0.7% (2/286) of patients had negative results across all serum protein electrophoresis (SPE), immunofixation electrophoresis (IFE), and free light chain (FLC) analyses, while 27.4% (110/401) had negative results in both serum SPE and IFE. This underscores the importance of performing FLC assays for screening. Bone marrow fluorescence in situ hybridization (FISH) performed in 65 patients showed that the most common chromosomal abnormalities were 1q21+ (27.7%) and del(13q14) (21.5%). This differs from Western studies where (11;14) is the most prevalent.[4] Most patients were categorized under Mayo 2004 with European modification (Mayo 2004) and Mayo 2012 staging systems as IIIa/IIIb (74.7%, 254/340) and III/IV (73.2%, 183/250), respectively, suggesting late diagnosis. These figures highlight the need for improving early diagnosis. We split the study population into pre-2018 (2010–2017) and post-2018 (2018–2022) subgroups [Figure 1A]. Before 2018, alkylating agents and immunomodulatory imide drugs (IMiDs)-based regimens were preferred as first-line treatments. However, bortezomib-based regimens began gaining traction in 2016 and achieved mainstream acceptance after 2018. Daratumumab emerged as the first-line treatment in 2020. Its inclusion in the NMIRL in 2022 led to a significant rise in its utilization, although the overall usage proportion remained low. The prevalence of patients receiving only supportive care has been decreasing since 2020, with the lowest figure reported in 2022. We analyzed key indicators in the pre- and post-2018 periods [Supplementary Table 2, https://links.lww.com/CM9/C143]. A decrease in the time from symptom onset to diagnosis in the post-2018 period (8.1 months vs. 7.1 months, P = 0.68), a significant shift in the proportion of patients receiving anti-plasma cell therapy (57.8% [96/166] vs. 67.3% [228/339], P = 0.04), and significant changes in the proportion of patients receiving alkylating agents, IMiDs, and bortezomib-based regimen were observed. These trends highlight how drug accessibility and affordability influence treatment patterns within China’s healthcare system.Figure 1: (A) Changes in the number of pathologically diagnosed patients, proportion of first-line treatment, and healthcare policy from 2010 to 2022. The period from 2010 to 2017 is categorized as pre-2018, and 2018 to 2022 as post-2018. This division is based on the increase in pathologically diagnosed patients, the establishment of amyloidosis or neoplasm MDTs across participating centers, the release of the national list of rare diseases in 2018, and the inclusion of bortezomib in the NMIRL in September 2017. (B–E) Kaplan–Meier graphs of OS analyzed according to various factors: (B) different periods, (C) presence or absence of MDT management, (D) hematological response at 6 months after first-line treatment initiation, and (E) first-line treatment selection. ASCT: Autologous stem cell transplantation; CR: Complete response; IMiDS: Immunomodulatory imide drugs; MDTs: Multidisciplinary teams; NMIRL: National medical insurance reimbursement list; NR: No response; OS: Overall survival; PD: Progressive disease; PR: Partial response; VGPR:Very good partial response.For first-line treatment, the bortezomib-based regimen achieved a hematological overall response rate (ORR) of 77.8% (91/117), a complete response (CR) in 23.9% (28/117), a very good partial response (VGPR) in 29.1% (34/117), and a partial response (PR) in 24.8% (29/117) of patients. No response (NR) and progressive disease (PD) were observed in 22.2% (26/117) of patients [Supplementary Table 3, https://links.lww.com/CM9/C143]. These findings align with prospective data from the UK National Amyloidosis Centre.[5] The median time to achieve hematological responses was 3.0 (0.5–12.0) months. The bortezomib-based regimen achieved a rate of 48.5% (32/66) for cardiac response and 52.4% (22/42) for renal response [Supplementary Tables 4, 5, https://links.lww.com/CM9/C143]. The median time was 5.0 months and 7.0 months for cardiac and renal responses, respectively. The daratumumab-based regimen demonstrated a shorter median response time (one month) with a hematological CR rate of 60% (3/5), although the number of patients was minimal [Supplementary Table 3, https://links.lww.com/CM9/C143]. In 75 patients receiving second-line treatment, the daratumumab-based regimen was the most commonly used (37.3%, 28/75) [Supplementary Table 6, https://links.lww.com/CM9/C143]. Our findings underscore the importance of daratumumab as a second-line treatment for AL amyloidosis, showing a robust ORR of 88.9% (16/18) and a CR rate of 33.3% (6/18) with a median response time of 1 month [Supplementary Table 7, https://links.lww.com/CM9/C143]. These results are comparable to those of other study.[6] The rapid and profound hematological response highlights the significance of daratumumab in second-line therapy. The median follow-up period was 17 (range: 0–156) months, with a median OS of 28 (95% confidence interval [95% CI]: 22–40) months [Supplementary Figure 2, https://links.lww.com/CM9/C143], which is shorter than the US and European cohorts (28 months vs. 36 months and 48.8 months).[1,2] Although there is no statistically significant difference, an improvement trend in survival was observed in the later period, with a median of 29 months in the pre-2018 period and a median of 48 months in the post-2018 period at 5 years (P = 0.22; Figure 1B). Survival comparison between all patients receiving MDT management and those who did not revealed a significantly extended median OS in the post-2018 period (P = 0.001), with a median survival time that has yet to be reached, compared to a 28-month OS in the non-MDT group [Figure 1C]. In the post-2018 period, patients receiving anti-plasma cell therapy in the MDT group also showed improved OS compared to the non-MDT group, although the difference did not reach statistical significance [Supplementary Figure 3, https://links.lww.com/CM9/C143]. These results highlight the crucial role of MDT management in treating AL amyloidosis. Both Mayo 2004 and 2012 staging systems significantly distinguish the prognosis between early stage (stages I and II) patients and those with advanced stages (stages IIIa or IIIb and III or IV) [Supplementary Figure 4, https://links.lww.com/CM9/C143]. Survival analyses based on hematological remission at six months revealed significantly improved prognoses for patients achieving CR and VGPR compared to those with PR or NR and PD [Figure 1D]. Additionally, both cardiac and renal responses were associated with improved OS [Supplementary Figure 5, https://links.lww.com/CM9/C143]. Compared with supportive therapy, all anti-plasma cell treatments prolonged the patients’ OS. The bortezomib-based regimen significantly outperformed other treatments, with a median survival time not yet reached (intent-to-treat analysis, Figure 1E). Our data indicated that consolidative ASCT did not significantly enhance prognosis in patients achieving CR after chemotherapy (P = 0.53) [Supplementary Figure 6, https://links.lww.com/CM9/C143]. This finding continues to question the therapeutic role of ASCT in AL amyloidosis patients achieving hematological CR following induction chemotherapy, particularly considering the evolving role of minimal residual disease assessment. Patients with 1q21+ did not present with an inferior prognosis in our cohort, which primarily received bortezomib-based therapy [Supplementary Figure 7, https://links.lww.com/CM9/C143]. This study reports a large cohort of AL amyloidosis patients in Chinese mainland over a decade. This study revealed the real-world status of AL amyloidosis in China, highlighting longer diagnostic delays, different cytogenetic abnormalities, and shorter OS compared to Western countries. Nevertheless, significant improvements in early diagnosis and OS have been noted since 2018 because of improved therapeutic agents and MDT management. The study underscores the necessity for ongoing efforts to enhance access to diagnostic tests, increases awareness of this disease among healthcare institutions, and improves the availability and affordability of effective treatments to enhance early diagnosis, treatment choices, and prognoses of Chinese patients. Acknowledgements We thank the amyloidosis MDT, the Rare Disease Center at West China Hospital, Sichuan University, and all the collaborating medical centers involving in this study. Conflicts of interest YW received fees derived from research funding (AMY4002) from Janssen. The researchers conducted the data collection, analysis, and interpretation independently.