Treatment of immunoglobulin light chain (primary or AL) amyloidosis

Not all forms of amyloidosis are systemic. Some patients may present with a localized form and should not be treated with chemotherapy. Some patients with systemic amyloidosis may have secondary, familial, or dialysis-related types.These types are not responsive to chemotherapy. Immunoglobulin light chain (primary or AL) amyloidosis is a plasma cell dyscrasia. Suppression of light chain production translates to organ response, improved organ function, and improved quality of life. This review of the various available options for the treatment of systemic amyloidosis is designed to help the clinician determine which patients are candidates for stem cell transplantation and which should be treated with conventional chemotherapy. The role of the recently introduced novel agents in management of amyloidosis is also reviewed.     

Oral cyclic melphalan and dexamethasone for patients with AL amyloidosis

PurposeAggressive treatment of amyloid light chain (AL) amyloidosis with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. However, only selected patients with AL amyloidosis are eligible for HDM/SCT because of amyloid-associated organ dysfunction.Patients and MethodsWe report on 70 patients with AL amyloidosis treated with oral cyclic melphalan and dexamethasone.ResultsOf 48 evaluable patients who survived and returned for follow-up assessment, 6 patients (13%) achieved a complete hematologic response and 12 patients (25%) a partial hematologic response. Responses were non-inferior for patients receiving weekly “low-dose” dexamethasone compared with those receiving 4 day pulses. Median survival for the 70 patients has not yet been reached with a median follow-up of 17 months. Nineteen patients (27%) received additional treatment leading to improvement in survival.ConclusionMelphalan/dexamethasone can lead to hematologic responses and improvement in survival, particularly for those who can receive additional treatment for AL amyloidosis.     

Primary (AL) amyloidosis in plasma cell disorders

Primary (AL) amyloidosis is the most common form of systemic amyloidosis. The morbidity arises from extracellular deposition of immunoglobulin light chain (LC) fibrils in major organs, such as the kidneys, heart, and bowel. Organ dysfunction contributes to a high mortality and poor prognosis, with a median survival time of 1-2 years from diagnosis. Here, we present a 46-year-old man with an exceptional clinical course of an LC multiple myeloma with generalized amyloidosis, causing renal insufficiency, congestive heart failure, and complete intestinal necrosis. We have summarized recent knowledge on AL amyloidosis, its association with monoclonal gammopathies, clinical presentations, diagnostic tools, and treatment strategies. Our comprehensive overview of this rare and often fatal disease aims to increase the awareness of AL amyloidosis. This may facilitate earlier diagnosis, and thus allow initiation of prompt and specific therapies, which are indispensable in order to improve disease prognosis.     

Immunotherapy in systemic primary (AL) amyloidosis using amyloid-reactive monoclonal antibodies

Heretofore, treatment of patients with primary or light chain-associated (AL) amyloidosis has been directed toward reducing the synthesis of the amyloidogenic precursor protein through conventional or high-dose cytotoxic antiplasma cell chemotherapy. Although such efforts have extended survival, most often the prognosis remains exceedingly poor due to the persistence (or progression) of the pathologic deposits. The development of murine amyloid-reactive monoclonal antibodies (mAbs) has provided another therapeutic approach; namely, passive immunotherapy. These reagents, prepared against human light chain-related fibrils, recognize an epitope common to the beta-pleated structure of AL and other types of amyloid proteins and can effect rapid amyloidolysis when administered to mice injected with human AL amyloid extracts. One such prototypic antibody, the IgG1kappa mAb 11-1F4, has now been chimerized and is undergoing GMP production for an eventual phase I and II clinical trial in patients with AL amyloidosis. Demonstration of the therapeutic efficacy of this amyloid-reactive mAb would provide an important proof-of-principle that this form of immunotherapy also could benefit individuals with other types of inherited or acquired amyloid-associated disease.     

Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors

Blockade of programmed cell death ligand‐1 with durvalumab has shown efficacy and safety in large, international studies of patients with advanced solid tumors. A phase 1, non‐randomized, open‐label multicenter study was initiated to evaluate durvalumab in a Japanese population. The first part of this study used a standard 3 + 3 dose‐escalation design to determine the optimal dosing schedule of durvalumab. Primary objective was evaluation of safety and tolerability of durvalumab monotherapy. Secondary objectives were to evaluate maximum tolerated dose (MTD), immunogenicity, pharmacokinetics, and efficacy. Twenty‐two patients (median age, 61.5 years; range, 41‐76; 64% male) received durvalumab at doses of 1, 3, or 10 mg/kg every 2 weeks (q2w), 15 mg/kg q3w, or 20 mg/kg q4w. Twenty patients discontinued before completing 12 months of treatment as a result of progressive disease and two due to adverse events (AE). The most common treatment‐related AE (trAE) were rash (18%) and pruritus (14%); two patients had grade ≥3 trAE including one patient each with hyponatremia and hypothyroidism. No patient experienced a dose‐limiting toxicity (DLT) during the DLT evaluation period and the MTD was not identified. There were no AE leading to a fatal outcome during study treatment. Durvalumab showed dose‐proportional pharmacokinetics across the 1‐20 mg/kg dose range; incidence of positive titers for antidrug antibodies was 9%. One patient with lung cancer had a partial response and disease control rate at 12 weeks was 36%. In conclusion, durvalumab at the doses and regimens evaluated was safe and well tolerated in Japanese patients with advanced solid tumors.     

Impact of early response on outcomes in AL amyloidosis following treatment with frontline Bortezomib

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p < 0.005). At 1-month, patients with CR and iFLC < 20 mg/l had a significantly better survival compared to CR and iFLC > 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.Subject terms: Myeloma, Prognosis     

Biological features of the clone involved in primary amyloidosis (AL).

Primary light chain-associated amyloidosis (AL) is a plasma cell dyscrasia that causes morbidity via systemic tissue deposition of monoclonal light chains in the form of fibrils (amyloid). It is the most common form of systemic amyloidosis in Western countries and is rapidly fatal. Knowledge of the pathobiology of the underlying B cell clone is of primary importance for the design and optimization of therapeutic strategies.     

Daratumumab for relapsed or refractory AL amyloidosis with high plasma cell burden

Daratumumab, an anti‐CD38 antibody, is effective in AL amyloidosis with low tumor burden. Data of daratumumab treatment in patients with AL amyloidosis but high tumor burden (≥10% bone marrow plasma cells) are limited. We report retrospective data of 10 consecutive patients with high tumor burden treated with daratumumab for relapsed/refractory AL amyloidosis. The median age at diagnosis was 62.3 years; all patients had cardiac involvement, and six (60%) patients had renal involvement. Median bone marrow plasma cell infiltration was 15% (range 10%‐40%), and the median difference between involved and noninvolved free light‐chains (dFLC) was 446 mg/L (range 102‐1392 mg/L). Patients had a median of three prior lines of therapy, including bortezomib in all patients and lenalidomide in seven (70%) patients. The median time to first hematological response was 14 days (range 7‐28 days), and the median time to best hematological response was 64 days (range 7‐301 days). The hematological overall response was 90%, with high‐quality response (≥ very good partial remission [VGPR]) in 70% of the patients. Fifty percent of the patients had a cardiac response after a median of 3.8 months (range 0.7‐9.1). Infusion‐related adverse events ≤ grade 2 occurred in seven (70%) patients and grade 3 adverse events in one patient. After a median follow‐up time of 10 months, eight (80%) patients continued to receive daratumumab. We conclude that daratumumab is a very effective and safe treatment option in AL patients with relapsed/refractory disease and high disease burden at diagnosis. Daratumumab leads to rapid disease control and improvement of organ function.     

Tolerability of Raltitrexed ('Tomudex') in elderly patients with colorectal cancer

PURPOSE: Colorectal cancer (CRC) is one of the major health problems of the Western world and the proportion of elderly patients with CRC is growing. Raltitrexed ('Tomudex'), a specific thymidylate synthase inhibitor, has shown efficacy and manageable toxicity in elderly CRC patients. In this retrospective study, the tolerability of raltitrexed in patients with CRC was examined in relation to age. PATIENTS AND METHODS: Toxicity parameters, graded according to World Health Organization criteria, were assessed in two patient groups: < 70 and > or = 70 years old. In total, 56% (50 out of 90) of patients treated with raltitrexed (3 mg/m2 as a 15-minute intravenous infusion every 3 weeks) were aged > 70 years (M:F 28:22; Eastern Cooperative Oncology Group performance status 0-1:2 38:12). RESULTS: Overall, 437 cycles of chemotherapy were administered and grade 3-4 toxicity was reported in < 10% of patients. There were no clinically significant differences between the two age groups, apart from grade 3-4 asthenia, which was reported by 6% and 0% of patients aged > or = 70 and < 70 years, respectively. This was in spite of a significantly lower calculated mean creatinine clearance in patients aged > or = 70 years compared with those patients < 70 years of age. CONCLUSION: The raltitrexed toxicity profile does not appear to be significantly influenced by age; however caution is recommended in the management of elderly patients, particularly in the presence of impaired renal function.     

Combination of erythropoietin and thalidomide for the treatment of anemia in patients with myelodysplastic syndromes

We investigated the therapeutic activity of recombinant erythropoietin (r-EPO) in association with thalidomide in 30 patients with myelodysplastic syndromes (MDS), previously treated with r-EPO (n.15, group A) or thalidomide (n.15, group B) as single agents, respectively, without any significant benefit on their anemia. Four patients of group A and three of group B (23.3%) achieved an erythroid response, according to International Working Group (IWG) criteria. After 12 weeks, responders of group A continued with thalidomide alone, those of group B with r-EPO alone. All responses were maintained, thus suggesting they were likely due to the second drug adjuncted (thalidomide for group A and r-EPO for group B), rather than to a combined effect. Our results do not support the hypothesis of a synergistic activity for the association of r-EPO and thalidomide on anemia of MDS. It seems, instead, that two populations of patients can be identified, according to their sensitivity to r-EPO or, alternatively, to thalidomide.     

沙利度胺联合MP方案治疗多发性骨髓瘤的疗效评价

 目的　比较沙利度胺联合美法仑+泼尼松方案（MPT）与美法仑+泼尼松方案（MP）治疗多发性骨髓瘤（MM）的疗效与患者不良反应。方法　采用回顾性分析,MPT组26例,美法仑每天9 mg／m2口服,第1天至第4天,泼尼松60 mg／m2,第1天至第4天,或者美法仑每天4 mg／m2口服,第1天至第7天;泼尼松每天40 mg／m2口服,第1天至第7天,28 d为1个疗程,沙利度胺自化疗开始持续给药,100～200 mg／d,每4周为1个疗程,MP组21例,美法仑及泼尼松用法用量同MPT组,6个疗程后评价总疗效。结果　MPT组的总有效率（ORR）为65.4 %,明显高于MP组的42.9 %（P＞0.05）;MPT组中位反应时间为2个月,MP组为3个月;MPT组患者治疗后血红蛋白及清蛋白升高明显高于MP组（P＜0.05）;MPT组不良反应的发生率高于MP组（P＜0.05）,但两组3度以上的不良反应差异无统计学意义;MPT组中位无进展生存时间（PFS）为11个月,2年PFS为66.18 %。结论　与MP方案相比,MPT方案可以提高MM患者的有效率,改善生活质量,延长生存时间,耐受性良好。     

Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2021

Immunoglobulin light chain amyloidosis (AL) commonly presents with nephrotic range proteinuria, heart failure with preserved ejection fraction, nondiabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea, and should be considered in patients presenting with these symptoms. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Herein we provide a review of established and investigational treatments for patients with AL amyloidosis and provide algorithms for workup and management of these patients.Subject terms: Myeloma, Chemotherapy     

轻链淀粉样变性的诊治更新及存在的问题

轻链淀粉样变性(AL)主要是免疫球蛋白轻链错误折叠形成的淀粉样物质,引起人体多脏器损害的一种克隆性浆细胞病,其发生机制不清楚.临床上通常以患者心、肾等某一脏器衰竭为突出表现.治疗主要为美法仑联合地塞米松或硼替佐米等靶向新药化疗或进行自体干细胞移植治疗.疗效的判断不仅以血清游离轻链及M蛋白水平判断血液学反应,更要以氨基末端B型脑钠肽前体和肌钙蛋白I判断心脏等重要脏器功能改善情况.在新药时代,心脏受累是生存和预后的决定因素.AL的现代治疗,不仅要给予抗浆细胞的新药靶向治疗,更要结合抗淀粉样变治疗,以清除AL的伴侣蛋白.尽管治疗上有很多可喜进展,但也有不少问题亟待解决.     

沙利度胺联合奈达铂治疗非小细胞肺癌的临床疗效

目的探讨沙利度胺联合奈达铂治疗非小细胞肺癌(NSCLC)的临床疗效。方法选取2013年1月至2014年10月间收治的108例NSCLC患者作为研究对象,按照随机数字表法,将患者随机分为观察组和对照组,每组各54例。观察组患者采用奈达铂+沙利度胺治疗,对照组患者给予奈达铂治疗。比较两组患者的近期疗效、血清血管内皮生长因子(VEGF)、碱性成纤维生长因子(b FGF)、肿瘤坏死因子α(TNF-α)水平及不良反应。结果观察组患者近期治疗有效率为40.7%,与对照组(31.5%)比较,差异无统计学意义(P>0.05)。治疗后,观察组患者血清VEGF、b FGF、TNF-α水平均低于对照组,差异均有统计学意义(P<0.05)。观察组患者Ⅰ~Ⅱ度胃肠道不良反应发生率低于对照组,差异有统计学意义(P<0.05),而中性粒细胞减少、血红蛋白减少、血小板减少、肝功能损害等不良反应发生率差异均无统计学意义(均P>0.05)。结论沙利度胺联合奈达铂治疗NSCLC疗效确切,能够显著降低胃肠道不良反应发生率及血清VEGF、b FGF、TNF-α水平,临床上值得推广。     

Three patients with primary AL amyloidosis treated by high-dose melphalan with autologous peripheral blood stem cell transplantation

We present three long-term survivors treated with high-dose melphalan with autologous peripheral blood stem cell transplantation(auto PBSCT)for primary AL amyloidosis. Because melphalan toxicity is dose-related, patient age and the extent of organ involvement are very important factors for the success of high-dose melphalan treatment with PBSCT. The patients were therefore given high-dose melphalan using the risk-adapted approach to melphalan dosing. They received 3 courses of a vincristine, doxorubicin and dexamethasone(VAD)regimen, along with high-dose melphalan(100-200mg/m2)with auto PBSCT. There were no serious complications or transplantation-related mortalities. Patients survived for an average of 68 months(22-100 months)in partial response. A risk-adapted approach to melphalan dosing with PBSCT is an effective treatment in patients with primary AL amyloidosis.     

A comparative study of cyclophosphamide,thalidomide and dexamethasone (CTD) versus bortezomib and dexamethasone (BDex) in light-chain amyloidosis

BackgroundCyclophosphamide, thalidomide, and dexamethasone (CTD) or bortezomib and dexamethasone (BDex) show substantial efficacy in patients with amyloid light-chain (AL) amyloidosis, especially in Chinese patients. Currently, both regimens are recommended as primary treatment options for AL amyloidosis, but no comparative study has been reported.MethodsWe retrospectively evaluated the outcomes of 81 AL patients who received CTD (n = 42) or BDex (n = 39) and used Mayo stage 2012 to match 26 pairs of patients.ResultsIn the whole cohort, the overall hematologic responses were 86% vs 91% in the CTD and BDex groups, including a complete response of 56% vs 71% based on an intention-to-treat (ITT) analysis. One- and 2-year overall survival (OS) was 90.2% and 81.7% with CTD, and 87.6% and 82.7% with BDex. After matching, BDex regimen induced a significantly deeper and more rapid hematologic response over CTD, but no statistically significant difference in OS (ITT analysis, P = 0.24; 6-month landmark analysis, P = 0.48). Cardiac response rates were similar, while there was a trend for higher renal responses in patients treated with BDex (68% vs 44%, P = 0.09). Additionally, BDex was associated with significantly improved survival in patients with advanced disease (Mayo stage III or worse; P = 0.009). Patients treated with BDex reported more episodes of severe hematologic toxicity and diarrhea.ConclusionsCTD and BDex are effective treatments for Chinese patients with AL amyloidosis, but BDex regimen appears superior to CTD in achieving a more rapid and deeper clonal response, and in improving OS in patients with advanced disease.