Systemic Immunoglobulin Light Chain Research Articles

Immune Checkpoint Expression Patterns on T Cell Subsets in Light-Chain Amyloidosis: VISTA, PD-1, and Tigit As Potential Therapeutic Targets

Abstract Background: Systemic immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare plasma cell dyscrasia with a poor prognosis. T-cell exhaustion can lead to impaired T cell-mediated antitumor immunity, but there is limited information available regarding the T-cell immunodeficiency status in AL amyloidosis. This study aims to investigate the T-cell immune checkpoint expression patterns in AL amyloidosis and its relationship with clinicobiological characteristics. Methods: Using multi-color fluorescent flow cytometry, we examined the expression levels of V-domain immunoglobulin suppressor of T cell activation (VISTA), programmed death 1 (PD-1), T cell immunoglobulin and mucin-domain-containing-3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) on CD3+, CD4+, CD8+ T-cell, and regulatory T cell (Treg) in peripheral blood (PB) and bone marrow (BM) from 19 patients with newly diagnosed AL amyloidosis. We used 36 PB and BM samples from patients with newly diagnosed multiple myeloma (MM) and 19 PB and 10 BM samples from healthy individuals (HIs) as controls. Results: Our results showed that PB from patients with AL amyloidosis had significantly higher percentages of VISTA+ and PD-1+ subsets within CD3+, CD4+, CD8+ T cells and Tregs when compared to HIs. No statistical differences for frequency of VISTA+, PD-1+, Tim-3+ and TIGIT+ T-cell in BM were observed between the two groups. The percentages of double-positive VISTA+ PD-1+, VISTA+ Tim-3+, VISTA+ TIGIT+, PD-1+ Tim-3+ and PD-1+ TIGIT+ T cells in PB from the patients with AL amyloidosis were also considerably higher than those in the HIs. Moreover, we discovered that the patients with renal involvement had greater percentages of PD-1+ or TIGIT+ subsets within CD3+, CD4+ T cells and Tregs than the individuals without renal involvement. Additionally, PD-1+CD3+%, PD-1+CD4+%, and PD-1+Treg% were found to be positively correlated with 24-hour proteinuria levels. Furthermore, we observed that the AL amyloidosis patients had significantly higher counts of PD-1+ Treg in PB than the MM patients, while the MM patients had significantly higher counts of TIGIT+ subsets within CD3+, CD4+ and CD8+ T cells than the AL amyloidosis patients. Conclusions: Our findings suggest that there are elevated proportions of VISTA+ and PD-1+ T cells in PB of AL amyloidosis patients, which are indicators of an immunosuppressive milieu. The rise in PD-1+ or TIGIT+ T cells was associated with renal damage. Notably, MM and AL amyloidosis have very distinct immunosuppressive patterns based on immune checkpoint alteration. Overall, VISTA, PD-1, and TIGIT may be considered as potential targets for reversing T cell exhaustion and enhancing T cell activity in AL amyloidosis.

Peripheral Nervous, Hepatic, and Gastrointestinal Endpoints for AL Amyloidosis Clinical Trials: Report from the Amyloidosis Forum Multi-organ System Working Group.

Systemic immunoglobulin light chain (AL) amyloidosis is a heterogeneous rare disease driven by a destructive monoclonal gammopathy and typified by misfolded immunoglobulin light and/or heavy chains which aggregate and deposit in organs as insoluble amyloid fibrils. Disease heterogeneity is driven by the degree of multi-systemic involvement; cardiac, renal, neurological, and gastrointestinal (GI) systems are affected to varying degrees in different patients. While prognosis is primarily driven by hematologic response to treatment and outcomes associated with cardiac events and overall survival, the involvement of the peripheral nervous, hepatic, and GI systems can also have a significant impact on patients. The Amyloidosis Forum ( https://amyloidosisforum.org ) is a public-private partnership between the nonprofit Amyloidosis Research Consortium ( www.arci.org ) and the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research formed to advance drug development for the treatment of systemic amyloid disorders. A series of virtual workshops focused on the development of novel, patient-relevant endpoint components and analytical strategies for clinical trials in AL amyloidosis. This review summarizes the proceedings and recommendations of the Multi-Systemic Working Group which identified, reviewed, and prioritized endpoints relevant to the impacts of AL amyloidosis on the peripheral nervous, hepatic, and GI systems. The Working Group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the FDA, Medicines and Healthcare products Regulatory Agency (MHRA), and pharmaceutical companies. Prioritized neuropathy/autonomic endpoints included a modified form of the Neuropathy Impairment Score (NIS + 7) and the Composite Autonomic Symptom Score (COMPASS-31), respectively. Alkaline phosphatase was identified as the most relevant indicator of liver involvement and disease progression. Following extensive review of potential GI endpoints, the Working Group identified multiple exploratory endpoints. These recommended components will be further explored through evaluation of clinical trial datasets and possible integration into composite endpoint analysis.

Prognostic implications of clinical phenotype and severity of cardiac involvement in patients presenting with immunoglobulin light chain amyloidosis

Abstract Background Patients with systemic immunoglobulin light chain (AL) amyloidosis may present with a wide array of signs and symptoms due to the multi-systemic organ involved. The presence of cardiac involvement is the key determinant of survival. Cardiac magnetic resonance (CMR) has the unique ability to measure the continuum of cardiac amyloidosis (CA) infiltration providing a deep characterisation from early CA involvement to severe degree of CA burden. Purpose The aim of this study was to characterise the clinical profiles and the severity of organ involvement in patients presenting with AL amyloidosis and to investigate implications for long-term outcome. Methods Patients newly diagnosed with AL amyloidosis at the National Amyloidosis Centre underwent comprehensive clinical, laboratory and instrumental work up, including CMR imaging with left ventricular (LV) mass, late gadolinium enhancement (LGE) and extracellular volume (ECV). The clinical phenotypes were classified in cardiac, renal and other according to the symptoms at presentation. The degree of CA was investigated by CMR: 0= no features of CA (normal LV mass, no LGE and normal ECV); 1=early cardiac amyloid infiltration (normal LV mass, raised ECV no LGE); 2= characteristic of CA with normal mass (diffuse subendocardial or transmural LGE, altered gadolinium kinetics and raised ECV); 3= characteristic of CA with elevated mass (diffuse subendocardial or transmural LGE and raised ECV). The study outcome was all-cause mortality. Results The study population included 241 AL patients presenting with cardiac and renal (22.8%, n=55), cardiac (28.2%, n=68), renal (33.2%, n=80) and other (15.8% n=38) phenotypes. During a median follow up of 33 (IQR 7–52) months, cardiac phenotype either in isolation or in combination with renal phenotype was associated with a higher rate of all-cause mortality compared to the others (p<0.001) (Figure). On CMR imaging, 43.2% of patients without cardiac phenotype (49%, n=118/241) had characteristic scans of CA (CMR grade 2 and 3) whilst 13.8% of patients with cardiac phenotype (51%, n=123/241) had no features of CA on CMR images (CMR grade 0) in (p<0.001). With Kaplan Meier analysis, the risk of all-cause death increased in patients with characteristic features of CA on CMR scan (Figure 1) and in patients with cardiac phenotype and features of CA on CMR scans compared to the others (both p<0.001) (Figure). At multivariable analysis, age at diagnosis (hazard ratio [HR] 1.03, p=0.009), clinical phenotype at presentation (HR 1.35, p=0.014) and ECV measured by CMR (HR 56, p<0.001) emerged as independent prognostic parameters. Conclusions Patients with newly diagnosed AL amyloidosis present most frequently with renal and cardiac phenotypes. CMR detects CA in >40% of patients with non-cardiac phenotype. ECV is an independent predictor of all-cause mortality across the full clinical spectrum of AL amyloidosis. Funding Acknowledgement Type of funding sources: None.

Systemic Immunoglobulin Light Chain Amyloidosis Presenting as Painful Penile Ulcers

Immunoglobulin light chain (AL) amyloidosis is a systemic form of amyloidosis that commonly affects the heart, kidney, liver, and nervous system. Penile involvement in AL amyloidosis is rare and thus often not considered in the differential diagnosis for penile ulcers. We report a case of an elderly man with nonhealing, painful penile ulcers who had AL amyloidosis with cardiac, renal, and liver involvement. His penile lesions were successfully treated with surgical resection of the amyloid deposits. Even after serologic relapse of his systemic amyloidosis, he has not had recurrence of his penile ulcers many years later.

Modified High-Dose versus High-Dose Melphalan Conditioning in Older Patients Undergoing Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light-chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m2) is considered in older patients because of concerns regarding tolerability. Age does not predict frailty, and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65-68) versus 69 years (range 65-76) in the HDM and mHDM groups, respectively. HR of ≥ very good partial response at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression-free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (P =.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in the HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies.

Intérêt du daratumumab dans l’amylose AL réfractaire chez une patiente de 96 ans

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+plasma cells, resulting in organ dysfunction. Cardiac involvement has a major prognostic value. Antiplasma cell chemotherapy reduces the synthesis of immunoglobulin light chains (precursors of amyloid deposits). We describe a case of AL amyloidosis in a 95-year-old patient. Our patient responded poorly to treatment with rituximab, cyclophosphamide-bortezomib-dexamethasone, and rituximab-bendamustine. Finally, the anti-CD38 antibody daratumumab was associated with the best hematologic responsiveness without significant adverse effects. In conclusion, our case suggests that daratumumab is an effective and well-tolerated alternative to chemotherapy in the treatment af AL amyloidosis in very elderly patients.

Adding Cyclophosphamide to Bortezomib and Dexamethasone was not Associated With Improved Outcomes of Patients With Newly Diagnosed Light Chain Amyloidosis: A Retrospective Study

IntroductionBefore 2021, the combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was one of the most used upfront therapy for systemic immunoglobulin light chain (AL) amyloidosis. Recently, daratumumab in combination with VCd resulted in improved outcomes compared to VCd. However, it's still unclear the role of cyclophosphamide in this combination. Materials and MethodsWe conducted this retrospective single-institutional study to compare the outcomes of upfront bortezomib and dexamethasone with or without cyclophosphamide (VD vs. VCd). ResultsOf 136 total patients, 62 received VD and 74 received VCd. The median age was 64 and the median number of organs involved was 2. Hematologic response was achieved among 73.4% patients in the VD arm and 85.9% in the VCd arm at 3 months (P = .15). Best organ response was not different between 2 arms (34.1% vs. 52.9% for VD and VCd arms, respectively; P = .28). After a median follow-up of 24.4 months, 2-year OS for VD and VCd arm was 70.6% and 84.6% respectively. The median overall survival was 70 months for VD arm and not reached for VCd arm (P = .30). There was no statistically significant difference in median time to next therapy (9.3 vs. 13.5 months for VD and VCd arms, respectively. P = .99). Conclusionthe addition of cyclophosphamide to VD was not associated with improved outcomes of patients with AL amyloidosis in this retrospective study.

Early relapse is an adverse prognostic marker in systemic immunoglobulin light chain (AL) Amyloidosis

Early relapse is an adverse prognostic marker in systemic immunoglobulin light chain (AL) Amyloidosis

Therapeutic Outcome of Lenalidomide-dexamethasone in Patients with Relapsed or Refractory Systemic Immunoglobulin Light Chain (AL) Amyloidosis : A Single-center Analysis and Review of the Literature

Therapeutic Outcome of Lenalidomide-dexamethasone in Patients with Relapsed or Refractory Systemic Immunoglobulin Light Chain (AL) Amyloidosis : A Single-center Analysis and Review of the Literature

P-024: Early relapse is an adverse prognostic marker in systemic immunoglobulin light chain (AL) Amyloidosis

<h3>Background</h3> Systemic Immunoglobulin light chain amyloidosis (AL) is a protein-misfolding disorder associated with an underlying monoclonal B-cell or plasma cell dyscrasia. There is little information on how response durability impacts outcomes. It is conceivable that early relapse may confer an adverse prognosis in AL, like in Myeloma. Here, we test the above hypothesis and analyse the factors affecting response durability in a cohort of AL patients treated with frontline Bortezomib. <h3>Methods</h3> All patients treated with frontline Bortezomib in 2010-2019 are included in the analysis. Patients with primary refractory disease, those with a continuing response but ≤ 24 months follow up, and those who received 2nd line therapy for reasons other than progression are excluded from the analysis. We defined early relapse (ER) as PFS ≤ 24 months. <h3>Results</h3> 560 patients are included in this analysis. 250 (44.6%) and 310 (55.4%) patients had ER and LR, respectively. The ER group had more advanced cardiac disease (p 20% (p=0.021), ≥ VGPR after 1st line (p 20%, and dFLC < 10 mg/l after treatment, we found serum monoclonal protein [OR 2.636 (95% CI 1.033-6.732), p=0.043] & dFLC < 10 mg/l [OR 0.122 (95% CI 0.063-0.235), p < 0.005)] were significant predictors of early relapse. <h3>Conclusions</h3> In conclusion, these data identify a high-risk group of patients who relapse early and have a poorer survival (irrespective of their initial response). The depth of response to the initial treatment is a critical determinant of response durability. The early relapses should be considered for clinical trials that can identify treatments with the potential to overcome the high-risk biology of the disease.

Urinary retinol binding protein predicts renal outcome in systemic immunoglobulin light-chain (AL) amyloidosis.

Renal risk stratification in systemic immunoglobulin light-chain (AL) amyloidosis is according to estimated glomerular filtration rate (eGFR) and urinary protein creatinine ratio (uPCR), the latter attributed to glomerular dysfunction, with proximal tubular dysfunction (PTD) little studied. Urinary retinol binding protein4 (uRBP), a low molecular weight tubular protein and highly sensitive marker of PTD, was prospectively measured in 285 newly diagnosed, untreated patients with systemic AL amyloidosis between August 2017 to August 2018. At diagnosis, the uRBP/creatinine ratio (uRBPCR) correlated with serum creatinine (r=0·618, P<0·0001), uPCR (r=0·422, P<0·0001) as well as both fractional excretion of phosphate and urate (r=0·563, P<0·0001). Log uRBPCR at diagnosis was a strong independent predictor of end-stage renal disease {hazard ratio [HR] 2·65, [95% confidence interval (CI) 1·06-6·64]; P=0·038}, particularly in patients with an eGFR >30ml/min/1.73m2 [HR 4·11, (95% CI 1·45-11·65); P=0·008] and those who failed to achieve a deep haematological response to chemotherapy within 3months of diagnosis [HR 6·72, (95% CI 1·83-24·74); P=0·004], and also predicted renal progression [HR 1·91, (95% CI 1·18-3·07); P=0·008]. Elevated uRBPCR indicates PTD and predicts renal outcomes independently of eGFR, uPCR and clonal response in systemic AL amyloidosis. The role of uRBPCR as a novel prognostic biomarker merits further study, particularly in monoclonal gammopathies of renal significance.

Current Updates on the Management of AL Amyloidosis.

Systemic immunoglobulin light chain (AL) amyloidosis is a rare but fatal disease. It results from clonal proliferation of plasma cells with excessive production of insoluble misfolded proteins that aggregate in the extracellular matrix, causing damage to the normal architecture and function of various organs. For decades, treatment for AL amyloidosis was based mainly on therapeutic agents previously studied for its more common counterpart, multiple myeloma. As the prevalence and incidence of AL amyloidosis have increased, ongoing research has been conducted with treatments typically used in myeloma with varying success. In this review, we focus on current treatment strategies and updates to clinical guidelines and therapeutics for AL amyloidosis.

Haematologic responses and survival do not significantly decrease with subsequent lines of therapy in systemic immunoglobulin light chain amyloidosis: results from an analysis of real-world longitudinal data.

Systemic immunoglobulin light chain amyloidosis (AL) is an incurable disorder, and the natural history is incompletely understood. In this study, we describe its natural history based on an analysis of real-world longitudinal data. All patients seen at the National Amyloidosis Centre, UK, between February 2010 and August 2019 and treated with up-front bortezomib are included. In all, 1276 patients received the first-line treatment; 259, 85, and 32 patients received second, third, and fourth treatment lines, respectively. Among patients requiring further treatment after the first line, 77·2% started the second line within two years of the first line; 50·5%, 50·6%, 40·1% and 40·6% of patients had achieved at least very good partial response after the first, second, third and fourth treatment lines. Median overall survival (OS) from first, second, third and fourth lines was 45 months, 56 months, 37 months and not reached, respectively (P=0·109). In summary, although relapses occur in AL amyloidosis, the outcomes and responses do not worsen with each subsequent relapse, making it attractive to design therapeutics with curative intent.

Retrospective Analysis of High-Dose Melphalan and Autologous Stem Cell Transplantation for Systemic Light-Chain Amyloidosis: A Single Center 63 Cases

[Background]High-dose melphalan and autologous stem cell transplantation (HDM/ASCT) show significant efficacy in systemic immunoglobulin light-chain (AL) amyloidosis. However, there have been few reports demonstrating efficacy of HDM/ASCT for AL amyloidosis patients in Asia, because of scarcity of AL amyloidosis. We retrospectively analyzed 63 cases of AL amyloidosis who received HDM/ASCT.[Patients and methods]We retrospectively analyzed 63 patients with AL amyloidosis who received HDM and ASCT between 2006 and 2017. Patients with plasma BNP<1000 pg/ml and <IVST 15mm were determined transplant eligible from 2007. The median age was 54 years old (range, 32-70). Cardiac, renal and gastrointestinal involvement were 24(38.1%), 42(66.7%) and 29(48%) patients, respectively. The percentage of more than 2 organ involvement was 69.8%. Cardiac response was defined as more than 30% of BNP decline. Because NTproBNP was measured only in limited number of patients, we used BNP instead of NTproBNP to analyze cardiac response. Also, BNP was well correlated to NTproBNP (spearman correlation = 0.922). Hematological and kidney response was defined as previously described (Comenzo RL et al, Leukemia, 2012). Briefly, a difference between the involved FLC and uninvolved FLC of 50mg/dl and more than 0.5g of 24-hour urine protein were defined as measurable for hematological and renal response.[Results]2-year and 4-year overall survival was 88.2% and 80.9%, respectively. Cardiac response was achieved in 9 of 22(40.9%). Hematological responses were evaluated in 25 cases and were 15(60%) sCR, 3(12%) VGPR and 6(24%) PR. More than 11mm of IVST affected worse OS(p=0.032) in line with previous reports. Also, more than 1mg/dl of serum creatinine (sCre) showed worse OS (p=0.022).Mortality within 100 days after ASCT was observed in 5 patients (1 MOF, 1 arrhythmia, 1 heart failure and 2 infection). 4 out of 5 patients showed cardiac involvement (median BNP value = 732.3).[Conclusions]Our analysis revealed comparable OS rate with other institutions in US and EU countries. Patients with cardiac involvement and higher sCre level showed worse prognosis. More than 11 mm of interventricular septum thickness (IVST) affected worse OS. Careful patient selection and experienced management are important for HDM/ASCT for AL amyloidosis. DisclosuresIshida:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria; ONO: Honoraria; Celgene: Honoraria. Suzuki:Bristol-Myers K.K: Honoraria; Novarltis: Honoraria; Celgen: Honoraria; Ono: Honoraria; Fujimoto: Honoraria; Takeda: Honoraria.

Autologous Stem Cell Transplant in the Era of Bortezomib-Based Induction for AL Amyloidosis Results in Improved Hematologic Response Rates: a Single Institution 11 Year Experience

Introduction: The current standard of practice for patients with systemic immunoglobulin light chain amyloidosis (AL) if transplantation-eligible is to proceed directly to high-dose melphalan (HDM) and autologous stem cell transplant (ASCT) without induction therapy. This approach has been associated with higher response rates and improved overall survival compared to chemotherapy alone. However multiple recent studies have shown the merits of bortezomib induction in AL patients who are transplantation-eligible and ineligible, and it is also increasingly used when significant bone marrow clonal plasma cells are present. These therapies have shown to be well-tolerated with favorable hematologic and organ responses, often enabling patients who were originally transplantation-ineligible to become eligible. The purpose of this study is to update our previously performed retrospective analysis of a single-institution population of patients with AL treated with bortezomib induction followed by HDM + ASCT.Methods: All patients with biopsy-confirmed AL who underwent HDM + ASCT at Oregon Health and Science University from 2006 to 2017 were included (n=53). Organ involvement and responses were assessed using the consensus criteria reported by the Roundtable on Clinical Research in Immunoglobulin Light-chain Amyloidosis. Institutional eligibility criteria for performing HDM + ASCT for AL patients included: Eastern Cooperative Oncology Group performance status ≤2, left ventricular ejection fraction >45%, New York Heart Association class <3, cardiac biomarker stage 1 or 2, carbon monoxide diffusing capacity >50%, and serum creatinine ≤3.0 mg/dL unless receiving dialysis. Patients received melphalan 200 mg/m2 or dose-reduced melphalan (100-140 mg/m2) for those at higher risk.Results: Of the 53 total patients, 13 proceeded directly to ASCT after diagnosis, whereas 34 received a bortezomib-containing induction regimen (increased from 12 in our previous study), and 6 received some other form of induction treatment (Table 1). Twenty-three patients received dose-reduced melphalan prior to ASCT. Twenty-five patients had cardiac involvement. Two patients (3.7%) died within 100 days after ASCT (one due to exsanguination from AL-involved splenic rupture, the other due to congestive heart failure). The overall hematologic (ORR) and organ response rates (OR) in the entire cohort after ASCT were 85% and 67%, respectively. ORR was 94% in the group that received bortezomib induction compared to 69% in the group that received no induction (p=0.04); OR in these groups were 77% and 54%, respectively (p=0.17). The mean time to maximum hematologic response was significantly shorter in those who received bortezomib induction compared to no induction (3.4 months vs. 16.8 months, p<0.0001). The overall cardiac response rate was 65.0%, with a rate of 71.4% in those pre-treated with bortezomib versus 43% in those who did not receive induction therapy (p=0.35). With a median follow-up of 2.9 years, 3-year progression-free (PFS) and overall survival (OS) in the entire cohort were 62% and 82%, respectively (Figure 1); in those with cardiac involvement, these rates were 59% and 83%, respectively. 3-year OS (Figure 2) in the bortezomib-induction group was 87% compared to 77% in the group that received no induction (p=0.22), 3-year PFS (Figure 3) in these groups were 61% vs. 69%, respectively (p=0.52)Conclusion: With the update of our institutional analysis, we have continued to observe that bortezomib-based induction is well-tolerated in patients with and without cardiac involvement and is associated with higher ORR and shorter time to hematologic response compared to those who receive no induction. In our analysis, bortezomib-based induction did not significantly impact OR, cardiac response rate, PFS, or OS, but these are likely limited by sample size and short follow-up time. Our results otherwise appear comparable to those seen at other major transplant centers. These findings therefore continue to support the emerging roles for bortezomib-based induction regimens for the purposes of improving response and even increasing eligibility for patients to safely undergo HDM + ASCT. Larger scale analyses in the form of prospective multi-center trials would be beneficial to further study these roles. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Role of Light Kappa and Lambda Chains in Heart Function Assessment in Patients with AL Amyloidosis.

There are reports indicating that myocardial dysfunction in systemic immunoglobulin light chain amyloidosis (AL amyloidosis) stems not only from the amyloid deposit in the organ but also the cardiotoxicity of the amyloid precursor free light chains (FLCs) circulating in the blood. The aim of the study is to analyze the role of sFLC κ and λ in the assessment of heart involvement and the degree of myocardial damage in AL amyloidosis. The study involved 71 patients diagnosed with primary AL amyloidosis. The relationship between sFLC concentrations and cardiac biochemical and echocardiographic parameters was assessed. The median concentrations of N-terminal pro b-type natriuretic peptide(NT-proBNP) and troponin I (TnI) were significantly higher in patients with amyloids formed from monoclonal λ chains compared to patients with monoclonal κ proliferation. In patients with heart involvement by amyloids formed from monoclonal FLC, the study demonstrated a statistically significant positive correlation between the concentration of monoclonal antibody λ chain and TnI (R = 0.688; p < 0.05), NT-proBNP (R = 0.449; p < 0.05), and the value of diastolic dimension of the interventricular septum (IVS; R = 0.496, p < 0.05). The above data indicate that the presence of monoclonal λ chains in patients with AL amyloidosis may be associated with more severe damage to cardiomyocytes and dysfunction of the myocardium.

Daratumumab plus CyBorD for patients with newly diagnosed light chain (AL) amyloidosis.

Primary systemic immunoglobulin light chain (AL) amyloidosis is caused by a plasma cell clone of, usually low, malignant potential that expresses CD38 molecules on their surface. Treatment of AL amyloidosis is based on the elimination of the plasma cell clone. The combination of cyclophosphamide–bortezomib–dexamethasone (CyBorD) is the most widely used and is considered a standard of care; however, complete hematologic response rates and organ response rates remain unsatisfactory. Daratumumab, an anti-CD38 monoclonal antibody, has demonstrated encouraging results, with rapid and deep responses, in patients with relapsed or refractory AL amyloidosis as monotherapy with a favorable toxicity profile. The large phase-III, randomized, ANDROMEDA study evaluated the addition of daratumumab to CyBorD in previously untreated patients with AL amyloidosis and demonstrated that addition of daratumumab can substantially improve hematologic complete response rates, survival free from major organ deterioration or hematologic progression, and organ responses. In this review, we discuss the role of daratumumab in the treatment of AL amyloidosis, its mechanism of action, and the results of ANDROMEDA study that led to the first approved therapy for AL amyloidosis.

Modified High Dose Versus High Dose Melphalan Conditioning in Older Patients Undergoing Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis

Introduction: High dose melphalan and autologous stem cell transplantation (HDM/SCT) results in deep and durable responses and prolonged survival in highly selected patients with systemic immunoglobulin light chain (AL) amyloidosis. HDM/SCT is offered to select patients &amp;gt;65 years but melphalan dose is often reduced due to concerns for tolerability and toxicities in older patients. However, older adults are a diverse population and chronological age alone does not accurately predict chemotherapy tolerance. While both melphalan 140 mg/m2 (MEL-140) and 200 mg/m2 (MEL-200) are commonly used in clinical practice, there are very few studies comparing these two doses in older patients. Available studies suggest that MEL-140 may be associated with worse event-free survival and progression-free survival, but it is unclear whether this is confounding for increased co-morbidities and frailty in this group. We report transplant-related toxicities and outcomes in patients &amp;gt;65 years undergoing first HDM/SCT with MEL-140 versus MEL-200 within 12 months of diagnosis of AL amyloidosis. Methods: We analyzed transplant-related toxicities and outcomes of patients &amp;gt;65 years who received first HDM/SCT within 12 months of diagnosis between January 2011 and June 2020. We excluded patients receiving additional conditioning agents and those undergoing tandem or second transplantation. Patients were stratified based on melphalan dose. All statistical analyses were performed using GraphPad Prism version 8©. Independent (unpaired) t tests with unequal variance and a 95% confidence interval were used to calculate the two-tailed p values for continuous variables. Chi-squared tests were used to compare categorical variables. Hazard ratios (HR) and odds ratios (OR) with 95% confidence intervals (CI) and p values are reported. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) and log-rank tests were used to compare the survival measurements of each group. In this cohort, PFS was defined as the time from SCT to hematologic progression, next line of therapy and/ or death, whichever came first. Transplant-related mortality was defined as death occurring within 100 days of SCT. Results: Forty patients were included in the final analysis with a median follow up of 55.0 months (range 7 - 109, n = 18) for surviving patients in both groups. Table 1 displays patient and disease characteristics, transplant-related toxicities, 2-year PFS and median OS. Patients receiving MEL-140 were older (69 versus 66 years, p &amp;lt;0.0001) and more likely to be male (82.6% versus 47.1%, p 0.0383). Karnofsky performance status (KPS) was similar in both groups. Median number of organs involved was 2 with 91.3% and 82.4% of patients having renal involvement in the MEL-140 and MEL-200 groups, respectively. For patients who underwent induction therapy with anti-plasma cell agents, 22.2% treated with MEL-140 and 50.0% treated with MEL-200 were in &amp;gt;VGPR prior to HDM/ SCT (p 0.3348). There was no transplant-related mortality observed in either group. Severe transplant-related toxicities (grade &amp;gt;3) were reported in 88.2% of the MEL-200 group versus 72.7% of the MEL-140 group (p 0.4260) but the frequency of various toxicities were different. Patients who underwent conditioning with MEL-200 were significantly more likely to experience febrile neutropenia, sepsis and infections (88.2%, n = 15 versus 50.0%, n = 11; OR 0.13, 95% CI 0.03 - 0.73, p 0.0173 [Table 2]). Notably, the 2-year PFS was almost twice as long in the MEL-200 group (82.5% versus 42.6%, p 0.0534 [Figure 1]). The median PFS was 12.1 months in the MEL-140 group but was not reached in the MEL-200 group. There was no difference in median OS among the two groups (not reached, p 0.1454). Conclusion: Our study results suggest that highly selected patients ≥65 years with good performance status can safely undergo melphalan at a dose of 200 mg/m2 prior to stem cell transplantation in AL amyloidosis although there may be an increased risk of febrile neutropenia, sepsis and infections. Additionally, the melphalan conditioning dose 140 mg/m2 is potentially associated with a significantly shorter progression-free survival than 200 mg/m2 in older patients undergoing HDM/SCT for AL amyloidosis. Disclosures Sanchorawala: Takeda: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents &amp; Royalties; Prothena: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

系统性免疫球蛋白轻链型淀粉样变性的治疗进展

系统性免疫球蛋白轻链型淀粉样变性的治疗进展

The role of three-dimensional speckle tracking imaging in the diagnosis of immunoglobulin light-chain cardiac amyloidosis with normal left ventricular ejection fraction

Objective To explore the value of three-dimensional speckle tracking imaging (3D-STI) in the diagnosis of immunoglobulin light-chain cardiac amyloidosis(AL-CA) patients with normal left ventricular ejection fraction (LVEF). Methods A total of 92 consecutive patients diagnosed with systemic immunoglobulin light chain amyloidosis(sAL) and with normal LVEF from October 2014 to January 2018 in Xijing Hospital were enrolled.Based on the diagnostic criteria of cardiac involvement, the patients were divided into AL-CA group (52 cases) and immunoglobulin light chain amyloidosis (AL) group (40 cases). The clinical data and serological markers of the patients were collected, the conventional echocardiography and full-volume three dimensional dynamic images were acquired, left ventricular global longitudinal strain (GLS), global radial strain (GRS), global circumferential strain (GCS), and global area strain (GAS) were analyzed using off-line TomTec software. The differences between the two groups were compared. Results Compared with the AL group, the NT-proBNP of AL-CA group was significantly higher (P 0.05). Compared with the AL group, the maximal left ventricular wall thickness, left ventricular mass index, left atrial volume index, and E/e′ in the AL-CA group were significantly increased (all P 0.05). Compared with the AL group, GLS, GAS, and GRS were significantly lower in AL-CA group (all P 0.05). The ROC curve analysis showed that the cut-off values discriminating cardiac involvement were 16.09% for GLS, 36.54% for GAS and 31.90% for GRS. Conclusions 3D-STI measurements of left ventricular myocardial mechanics could detect cardiac involvement in patients with sAL amyloidosis, and provides a new method for diagnosis of AL-CA. Key words: Echocardiography; Three-dimensional speckle tracking imaging; Immunoglobulin light-chain cardiac amyloidosis; Strain