Combination of bortezomib in the induction, conditioning and consolidation with autologous hematopoietic stem cell transplantation in patients with immunoglobulin light chain amyloidosis
Authors: Xianghua Huang, Chengcheng Fu, Lijuan Chen, Wencui Chen, Guisheng Ren, Jinzhou Guo, Liang Zhao, Caihong Zeng, Haitao Zhang, Dehua Gong, Qiang Ren, Zhihong Liu
Journal: American Journal of Hematology (2019)

Immunoglobulin light chain (AL) amyloidosis is the most commonly diagnosed form of systemic amyloidosis. Autologous hematopoietic stem cell transplantation (ASCT) remains the primary treatment for eligible patients with AL amyloidosis because of its excellent efficacy and a marked reduction in toxicity.1 Recently, it has been shown that novel agents such as bortezomib, which can be administered prior to the procedure, could increase the response rates following ASCT.2, 3 We also found that bortezomib in combination with dexamethasone (BD) followed by ASCT can significantly improve both the hematological and organ response rates of Al amyloidosis patients compared to ASCT alone.4 Thus, we conducted this trial to evaluate the efficacy and safety of bortezomib in combination with ASCT in the induction, conditioning and consolidation of patients with newly diagnosed AL amyloidosis. In this open-label, prospective, nonrandomized trial (ClinicalTrial.gov Identifier: NCT01273844), newly diagnosed patients with AL amyloidosis who met the eligibility criteria for ASCT were enrolled. The trial was approved by the institutional ethical review board of Jinling Hospital in accordance with the Guidelines for Good Clinical Practice and the Declaration of Helsinki. All the patients or their guardians provided written informed consent. All the patients were diagnosed AL amyloidosis by renal biopsy, typed by immunofluorescence, and had evidence of an underlying clonal plasma cell dyscrasia. Patients received two standard 21-day cycles of BD induction therapy and prophylaxis with an antiviral medication. After two cycles of BD therapy, the collection of peripheral blood stem cells (PBSCs) was completed within 4 weeks and a minimum collection of 2 × 106 CD34+/kg body weight was required. Patients received PBSCs infusion 8 weeks after collection (recorded as day 0), while melphalan (day −2) at a dose of 140 or 200 mg/m2 (dose chosen according to the degree of risk for patients) and bortezomib 1 mg/m2 (days −6, −3, +1, +4) were given during the ASCT procedure. Four additional 21-day cycles of bortezomib treatment (with a dose of 1.6 mg/m2 on day 1 and 8 of the cycle) were conducted as a consolidation therapy during the recommended 60-90 days after ASCT. Patient visits were scheduled for every 3 months until at least month 24. Hematologic and organ responses were evaluated according to the consensus criteria of the International Society of Amyloidosis published in 2005 and updated in 2012.5 The primary outcome was complete response (CR) rate at 12 months post-ASCT. From March 2011 to September 2014, 21 patients (13 males/8 females; median age: 51 years, range 37-61) were included in this study. The median follow-up time was 53 months (range: 36-80 months). Lambda clonal plasma cell dyscrasia was exhibited in 90.4% patients (19/21). The performance status was ECOG <2 in 85.7% of cases (18/21), and the median number of organs involved was two (range 1-3). Renal involvement was present in all subjects; 15 patients were in renal stage I, six patients were in renal stage II, and no patients were in renal stage III according to the validated staging system proposed by Palladini et al.6 There were 16 patients (71.2%) with nephrotic range proteinuria and the mean proteinuria was 4.07 g/24 hours. Ten patients (47.6%) had cardiac involvement. The proportion of patients with Mayo 2004 stages I, II, and III were 52.4%, 23.8% and 23.8%, respectively, and none were at Mayo 2012 stage IV. More details about the patient's characteristics at baseline are described in Supporting Information Table S1. All 21 patients enrolled in this trial received two cycles of BD induction therapy. During the ASCT treatment phase, one patient dropped out after induction therapy. Fifteen patients received 200 mg/m2 melphalan whereas five patients received 140 mg/m2 melphalan. The median number of stem cells collected was 6.13 × 106 CD34+/kg (range: 3.1-9.9 × 106 CD34+/kg), and the median granulocyte and platelet engraftments were 10 days (range: 9-12) and 12 days (range: 10-14), respectively. Fifteen patients completed four additional 21-day cycles of bortezomib treatment after ASCT, two patients did not receive additional consolidation therapy and three patients discontinued bortezomib consolidation therapy after two cycles due to peripheral neuropathy. During the whole treatment phase, the dose of bortezomib was reduced in eight patients due to grade 3 adverse events. The hematologic response and organ response rate are summarized in Supporting Information Table S2. The overall response (OR) rate after induction therapy of two cycles of BD was 57.1% and the CR rate was 28.5%. Eight (8/20, 40%) patients achieved hematologic CR after ASCT and 10 (10/20, 50%) after consolidation therapy. According to intention-to-treat (ITT) analysis, the CR rate was 47.6% (10/21) at 12 months after ASCT. The hematologic very good partial response (VGPR) rate reached 40% (8/20) after ASCT and 30% (6/20) after consolidation therapy. The OR rate was 90% (18/20) at 12 months after ASCT in evaluable patients and 85.7% (18/21) according to ITT analysis. The hematologic response rate of CR and VGPR increased from 52.4% to 80% after ASCT treatment. The OR rate was similar after ASCT, and the CR rate increased from 40% to 50% after consolidation therapy. Three patients had disease progression during the observational follow-up period. The changes in the differences between involved and uninvolved light chains (dFLC) during the treatment phase and observational follow-up period are shown in Figure 1A,B. The organ response rate of the evaluable patients increased over time after ASCT. The renal response reached 55% at 12 months, 66.7% at 24 months, and 66.7% at 36 months respectively after ASCT. Over the study period, the proteinuria and serum albumin improved significantly (Figure 1C,D). Similarly, cardiac response reached to 40% at 12 months, 50% at 24 months and 62.5% at 36 months, after ASCT. The median time to renal response was 8 months (4-36 months), and 6 months for cardiac response. Hematological improvement leads to the improvement of overall survival (OS). The median OS and progression-free survival (PFS) were not reached. The 5 years OS and PFS were 100% and 79.9%, respectively (Supporting Information Figure S1). Three patients had disease relapse after consolidation therapy that required additional treatment at a median time of 38 months. During the study period, 20 patients reported a total of 81 adverse events and the nonhematologic adverse events are summarized in Supporting Information Table S3. No deaths occurred during the treatment phase and the observational follow-up period. The most common grade 3 or higher nonhematologic adverse events related to bortezomib included herpes zoster infection (28.5%) and neuropathy (23.8%). Mucositis (28.5%) and febrile neutropenia (38.1%) were the two most common grade 3 or higher adverse events related to the ASCT treatment. Two patients experienced grade 4 adverse events during the treatment phase, and both recovered after therapy. One experienced an allergic shock at +7 days during ASCT, and one had severe pneumonia 3 months after ASCT. Peripheral neuropathy was the most common reason for bortezomib dose reduction or withdrawal. No treatment-related mortality (TRM) occurred in our study; this may be due to the risk-adapted approach with ASCT, the induction chemotherapy and the small proportion of enrolled patients having severe cardiac involvement. In conclusion, although the sample size of this study was too small to stratify according to hematologic responses or other variables, findings from this study demonstrated that combined bortezomib with ASCT in the induction, conditioning and consolidation with ASCT yielded a high hematologic and organ response rate with tolerable adverse events. Long-term follow-up results also indicate that OS and PFS of these patients has improved. A preliminary report on this trial was presented at the Annual Meeting of the American Society of Nephrology in November 2015. This work was supported by grants from the Key Research and Development Plan Project of Government of Jiangsu Province - Social Development Projects (BE2017721), and the Jiangsu Provincial Medical Youth Talent (QNRC2016895). This work was also supported by Xian Janssen Medical Fund. There are no conflicts of interest to disclose. Supplementary Material Table 1. Patient characteristics. Supplementary Material Tables 2: Hematological and organ responses. Supplementary Material Tables 3: Adverse events during different treatment phase (Grade 2-4) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.