Bone marrow plasma cell infiltration in light chain amyloidosis: impact on organ involvement and outcome

Abstract

Objectives: Prognosis of immunoglobulin light-chain (AL) amyloidosis depends mainly on the presence of cardiac involvement and the disease burden. A higher bone marrow plasma cell (BMPC) burden has been recognized as an adverse prognostic factor. The aim of our study was to analyze the correlation between the BMPC infiltration, clinical features and outcomes in patients with AL amyloidosis.

Methods: The clinical records of 79 patients with AL amyloidosis treated at a single institution.

Results: Median BMPC infiltration at diagnosis was 11% and significantly correlated with the serum free light-chain difference (p?<?.001). Patients with more than 10% BMPCs had more frequent cardiac involvement (86 vs. 63%; p?=?.015), a trend towards a higher early mortality (27 vs. 11%; p?=?.08) and a significantly shorter progression-free survival (PFS) (median of 18 vs. 48?months, p?=?.02) and overall survival (median of 33?months vs. not reached; p?=?.046). In the multivariate analysis, a BMPC infiltration over 10% retained its adverse prognostic value for PFS (HR?=?2.26; 95% CI, 1.048–4.866; p?=?.038). The use of new drugs seemed to overcome the negative prognostic impact of a higher BMPC infiltration.

Conclusion: Higher BMPC infiltration in AL amyloidosis might be associated with increased systemic organ damage, particularly cardiac involvement and is rarely related to the development of myeloma features.     

Multicentre versus single centre approach to rare diseases: The model of systemic light chain amyloidosis

Background.?Early diagnosis and supportive therapy are important in primary systemic amyloidosis (AL). In 1986, a national network was started in Italy to increase the awareness of medical professionals, achieve early diagnoses, and provide locally qualified care. We compared the AL patient population observed at a referral center, Mayo Clinic, with that recruited through the Italian network.

Methods.?All the patients diagnosed with AL between 1988 and 1998 at Mayo Clinic or in any of the centers of the Italian Amyloidosis Study Group were included.

Findings.?The median survival of Italian patients was 30 months versus 12 months in the Mayo cohort (P?<?0.001). Mayo Clinic patients were older (66.4 vs. 60.1 y, P?<?0.001). In the Italian cohort, dominant kidney involvement was more frequent (49.3% vs. 27.8%, P?<?0.001), while in the Mayo group more patients had dominant cardiac amyloidosis (37.4% vs. 27.8%, P?=?0.03). Italian patients were more likely to have kidney involvement without heart involvement (43.7% vs. 19.6%, P?<?0.001). Among Italian patients, 78.9% received alkylating agents versus 60.9% in the Mayo cohort (P?<?0.001). The multivariate analysis showed that age, performance status, dominant heart involvement, ??2 organs involved, and treatment with alkylating agents independently predicted survival. This study shows that AL patient populations may differ significantly between centers according to their accrual systems, with possible impact on treatment trials.     

Right ventricular longitudinal strain: a tool for diagnosis and prognosis in light-chain amyloidosis

Objectives: Light-chain (AL) amyloidosis can lead to an infiltrative cardiomyopathy with increased wall thickness (IWT) of very poor prognosis. Our primary aim was to analyse the right ventricle (RV) in patients with IWT to discriminate AL amyloidosis from IWT due to hypertrophic cardiomyopathy (HCM) or to arterial hypertension (HTN). Our secondary aim was to assess if RV dysfunction predicts overall mortality in cardiac AL amyloidosis.

Methods: We retrospectively and consecutively compared clinical, biological and echocardiographic data of 315 patients with IWT: 105 biopsy-proven AL amyloidosis patients, 105 patients with HCM and 105 patients with HTN. The prognostic value of these parameters was analysed in the AL amyloidosis group.

Results: Free-wall right ventricular longitudinal strain (FWRVLS) worse than ?21.2% discriminates AL amyloidosis [area under the curve (AUC)?=?0.744)] from patients with IWT due to other aetiologies. In AL amyloidosis, FWRVLS is the strongest echocardiographic prognostic marker with AUC =0.722 and ?16.5% as the optimal cut-off value, beyond which overall mortality increases significantly. It is also the only independent echocardiographic predictor of overall mortality (HR =1.113; 95%CI 1.029–1.204; p?=?.007), even when adjusted to the Mayo stage and global left ventricular longitudinal strain.

Conclusions: FWRVLS should be considered in the diagnostic and prognostic workup in light-chain amyloidosis.     

Haematological response and overall survival in two consecutive Dutch patient cohorts with AL amyloidosis diagnosed between 2008 and 2016

Abstract

Background: Although survival has improved in recent decades, the short-term prognosis of patients with immunoglobulin light chain (AL) amyloidosis remains grim. We aimed to assess overall survival (OS) of AL amyloidosis patients by comparing cohorts in two consecutive time periods.

Methods: Data were collected and compared on 126 patients from two tertiary referral centres in The Netherlands during the time periods 2008–2012 and 2013–2016.

Results: There was a non-significant trend to improved 6-month OS in the last cohort (78% vs. 67%, p?=?.216, crude odds ratio 1.66, 95%CI 0.74–3.70, adjusted odds ratio 2.22, 95%CI 0.88–5.56). Patients in this cohort had higher Mayo risk scores (stage III 40% vs. 24%, p?<?.001 and revised stage IV 14% vs. 11%, p?<?.001), higher use of bortezomib (50% vs. 30%), and better haematological response (complete response/very good partial response in 39% vs. 27%, p?<?.001). Diagnostic delay was similar in both time periods.

Conclusions: In the 2013–2016 cohort there was a trend toward improved 6-month OS, and an improved haematological response. Patients in this cohort had more advanced cardiac disease and received bortezomib more frequently, but diagnostic delay was similar to the 2008–2012 cohort. For further prognostic improvement, practitioners should be more alert, especially for cardiac amyloidosis.     

Prognostic impact of immunoparesis at diagnosis and after treatment onset in patients with light-chain amyloidosis

Objectives: Immunoparesis (IP) is a risk factor associated with an unfavourable outcome in several plasma cell disorders. It has been suggested that its presence in light-chain (AL) amyloidosis could be associated with worse prognosis. However, the relevance of IP after treatment has not been evaluated to date. The aim of this study was to determine the prognostic impact of IP at diagnosis and one year after treatment onset in patients with AL amyloidosis.

Methods: The clinical records of 69 patients with AL amyloidosis treated at a single institution from January 2006 to January 2016 were included in the study.

Results: IP was observed in 27.5% of patients at diagnosis. The presence of IP was associated with a lower probability to achieve very good partial response or better after first-line treatment (37.8% versus 62.2%; p?=?.04). However, only in the group of patients treated with autologous stem cell transplantation (ASCT), the presence of IP resulted in a shorter progression-free survival (PFS) (30.2?months versus not reached [NR]; p?=?.02) but not in overall survival (OS). Persistence of IP at one year after treatment onset was identified in only four (9.8%) of the 41 evaluable patients. In the ASCT group, the absence of IP at one year after treatment onset resulted in a longer median PFS and OS (NR versus 22.6?months; p?=?.006; and NR versus 35.2?months; p?Conclusion: IP at diagnosis has a negative impact on survival while its absence at one year after treatment is an independent marker for long-term survival.     

Bortezomib-based chemotherapy reduces early mortality and improves outcomes in patients with ultra-high-risk light-chain amyloidosis: a retrospective case control study

Background: Patients with amyloid light-chain (AL) amyloidosis who have advanced cardiac damage are at risk of premature mortality. Currently, bortezomib is the mainstay in the treatment of AL amyloidosis, but the benefits of bortezomib in patients with ultra-high-risk (2004 Mayo stage IIIb or 2012 Mayo stage IV) AL amyloidosis have not been proved definitively.

Methods: We performed a retrospective analysis of patients newly diagnosed with ultra-high-risk AL amyloidosis who received a bortezomib-based regimen or supportive treatment. We aimed to establish the effects of bortezomib on early mortality and long-term outcomes in this high-risk population.

Results: Patients receiving bortezomib-containing chemotherapy (n?=?62) and patients receiving no chemotherapy (n?=?24) were included. Median overall survival (OS) was 30?months in the bortezomib group and 2?months in the control group (p?<?.001), and median progression-free survival (PFS) was 15.8?months (bortezomib) and 2?months (control; p?<?.001). The early-death rate (within 6?months of treatment) was 32.3% (bortezomib) and 66.7% (control; p?<?.001). In a landmark analysis assessing outcomes in patients surviving beyond 6?months, the 2-year OS and PFS in the bortezomib group were 77.3% and 65.8%, respectively.

Conclusions: Bortezomib-based regimens can help to reduce early mortality and improve long-term survival in patients with ultra-high-risk AL amyloidosis.     

Predictive factors of outcomes in patients with AL amyloidosis treated with daratumumab

Daratumumab as a single agent (sDARA) or in combination with chemotherapies (cDARA) leads to impressive hematologic and organ responses in AL amyloidosis. However, predictive factors associated with outcomes, and optimal duration of therapy remain unclear. We analyzed 107 patients with AL amyloidosis treated with daratumumab between 2017 and 2020. The median overall survival (OS) was not reached while the median major organ deterioration progression free survival (MOD-PFS) was 36 months in the sDARA cohort and not reached in the cDARA cohort, respectively. Hematologic response > VGPR was achieved in 81% of patients receiving sDARA and 86% of patients treated with cDARA. Several predictive factors were identified on a univariate analysis, including NTproBNP >8500 pg/mL but only achievement of at least VGPR and presence of 1q21 gain were independently associated with MOD-PFS and OS on a multivariate analysis. Finally, patients receiving > 12 cycles had significantly longer MOD-PFS (30 vs.13 months; (p = .0018) and OS (NR vs. 15 months; p < .0001). NTproBNP > 8500 pg/mL, presence of 1q21 gain and shorter duration of therapy (≤ 12 cycles) are strong negative predictive factors for outcomes with daratumumab therapy in AL amyloidosis.     

Short‐ and long‐term outcomes of AL amyloidosis patients admitted into intensive care units

Amyloidosis is a rare and threatening condition that may require intensive care because of amyloid deposit‐related organ dysfunction or therapy‐related adverse events. Although new multiple myeloma drugs have dramatically improved outcomes in AL amyloidosis, the outcomes of AL patients admitted into intensive care units (ICUs) remain largely unknown. Admission has been often restricted to patients with low Mayo Clinic staging and/or with a complete or very good immunological response at admission. In a retrospective multicentre cohort of 66 adult AL (n = 52) or AA (n = 14) amyloidosis patients, with similar causes of admission to an ICU, the 28‐d and 6‐month survival rates of AA patients were significantly higher compared to AL patients (93% vs. 60%, P = 0·03; 71% vs. 45%, P = 0·02, respectively). In AL patients, the simplified Index of Gravity Score (IGS2) was the only independent predictive factor for death by day 28, whereas the Mayo‐Clinic classification stage had no influence. In Cox's multivariate regression model, only cardiac arrest and on‐going chemotherapy at ICU admission significantly predicted death at 6 months. Short‐term outcomes of AL patients admitted into an ICU were mainly related to the severity of the acute medical condition, whereas on‐going chemotherapy for active amyloidosis impacted on long‐term outcomes.     

Impact of minimal residual negativity using next generation flow cytometry on outcomes in light chain amyloidosis

We evaluated bone marrow minimal residual disease (MRD) negativity in 44 patients with light chain (AL) amyloidosis using next generation flow cytometry (sensitivity ≥1 × 10⁻⁵; median events analyzed: 8.7 million, range: 4.8 to 9.7 million). All patients underwent MRD testing in 2 years from start of therapy (median: 7 months). The overall MRD negative rate was 64% (n = 28). The MRD-negative rate after one-line of therapy was 71% (20/28). And, MRD negative rates were higher with stem-cell transplant as first-line therapy (86%, 18/21) vs chemotherapy alone as first-line treatment (29%, 2/7), P = .005. The MRD negative rate amongst patients in complete response was 75% (15/20), and in very good partial response, 50% (11/22). There were two patients in partial response/rising light chains (with renal dysfunction) who were MRD negative. There were no differences in baseline characteristics of MRD negative vs MRD positive patients, except younger age amongst MRD-negative patients. Patients with MRD negativity were more likely to have achieved cardiac response at the time of MRD assessment, 67% (8/12) vs 22% (2/7), P = .04. Renal response rates were similar in both groups. Progression free survival was assessed in the 42 patients achieving CR or VGPR. After median follow-up of 14 months, the estimated 1-year progression free survival in MRD negative vs MRD positive patients was 100% (26 patients, 0 events) vs 64% (16 patients, five events), P = .006, respectively. MRD assessment should be explored as a surrogate endpoint in clinical trials and MRD risk-adapted trials may help optimize treatment in AL amyloidosis.     

Multicentre versus single centre approach to rare diseases: the model of systemic light chain amyloidosis.

BACKGROUND: Early diagnosis and supportive therapy are important in primary systemic amyloidosis (AL). In 1986, a national network was started in Italy to increase the awareness of medical professionals, achieve early diagnoses, and provide locally qualified care. We compared the AL patient population observed at a referral center, Mayo Clinic, with that recruited through the Italian network. METHODS: All the patients diagnosed with AL between 1988 and 1998 at Mayo Clinic or in any of the centers of the Italian Amyloidosis Study Group were included. FINDINGS: The median survival of Italian patients was 30 months versus 12 months in the Mayo cohort (P<0.001). Mayo Clinic patients were older (66.4 vs. 60.1 y, P<0.001). In the Italian cohort, dominant kidney involvement was more frequent (49.3% vs. 27.8%, P<0.001), while in the Mayo group more patients had dominant cardiac amyloidosis (37.4% vs. 27.8%, P=0.03). Italian patients were more likely to have kidney involvement without heart involvement (43.7% vs. 19.6%, P<0.001). Among Italian patients, 78.9% received alkylating agents versus 60.9% in the Mayo cohort (P<0.001). The multivariate analysis showed that age, performance status, dominant heart involvement, >or=2 organs involved, and treatment with alkylating agents independently predicted survival. This study shows that AL patient populations may differ significantly between centers according to their accrual systems, with possible impact on treatment trials.     

Treatment patterns and outcome following initial relapse or refractory disease in patients with systemic light chain amyloidosis

We analyzed the outcomes following initial relapse or refractory disease in systemic light chain amyloidosis (AL) and the impact of type of therapy employed.A total of 1327 patients with AL seen at Mayo Clinic within 90 days of diagnosis, between 2006 and 2015, were reviewed. The study included 366 patients experiencing a documented hematological or organ relapse or refractory disease requiring start of second line therapy. Overall survival (OS) and time to next treatment (TTNT) were calculated from start of second line treatment.The median time to require second line treatment was 16.2 months (1‐93) from the start of first line therapy. At relapse, patients received proteasome inhibitors (PI; 45.1%), immunomodulators (IMiD; 22.7%), alkylators (9%), PI and IMiD combination (4.1%), autologous transplant (3.8%), steroids and other therapies (4.9%). Among these, 124 (33.9%) required change or reinstitution of therapy. The median time to require third line treatment was 31 months (95% CI; 24, 40.5) and the median overall survival (OS) was 38.8 months (95% CI; 29.6, 52.6) from the start of second line treatment. Retreatment with same therapy at relapse significantly reduced TTNT (22 m vs 32.3 m; P = .01) as compared to different therapy; but did not have any impact OS (30.8 m vs 51.1 m; P = .5). In conclusion, this study provides important information about outcomes of patients with AL who require second line treatment for relapsed/refractory disease . Treatment with a different therapy at relapse improves time to next therapy but does not impact OS.     

Prophylaxis of acute flares when initiating febuxostat for chronic gouty arthritis in a real-world clinical setting

Objective: Flare prophylaxis is recommended during urate-lowering therapy (ULT) despite lack of proven benefit especially when initiating febuxostat. We investigated if colchicine or steroids administration during initiation of febuxostat for chronic gouty arthritis reduces the frequency and/or severity of acute gout flares.

Methods: Patients with confirmed diagnosis of gout starting febuxostat were retrospectively studied. Frequency, severity, and length of flares were analyzed. Assessment of severity based on a visual analog scale (VAS).

Results: Two hundred and seventy-three patients were studied. The mean dose of colchicine and steroids was 0.53?±?0.15?mg PO QD and 7.55?±?1.30?mg prednisone equivalent PO QD; while the duration was 6.13?±?1.14 and 6.20?±?1.36 months, respectively. Subjects treated with colchicine and steroids suffered fewer total flares (0.30, 0.96 vs 2.47, p?=?.000), fewer flares from 0 to 3 months (0.26, 0.71 vs 1.72, p?=?.000), less severe flares assessed by VAS than those without prophylactic therapy (3.65, 3.49 vs 5.54, p?=?.000). Both total flares (p?=?.003) and flares from 0 to 3 months (p?=?.008) of the colchicine group were fewer than the steroids group. There were no significant differences in length of flares among groups (p?=?.815). Both colchicine and steroids were well tolerated.

Conclusion: The use of colchicine or steroids prophylaxis reduces the frequency and severity of acute gout flares during initiation of febuxostat for chronic gouty arthritis. Colchicine is superior to steroids in flares prophylaxis. Prophylactic therapy with colchicine 0.5?mg PO QD or steroids 7.5?mg prednisone equivalent PO QD for 6 months is suggested.     

Everolimus and long-term decline in renal function after liver transplantation: real-life experience with measured GFR

Abstract

Switching from calcineurin-inhibitors (CNI) to everolimus >6–12-months after liver transplantation (LT) seems inefficient in improving renal function, but whether everolimus halts further renal-function decline compared to low-dose CNI remains unclear. In a retrospective single-center study of everolimus after LT (2008–2016) with routine measured glomerular filtration rates (mGFR; ⁵¹Cr-EDTA- or iohexol clearance), we compared by propensity-score matching everolimus therapy to low-dose CNI therapy. The study comprised 36 patients with everolimus introduced on average 22?months post-LT (range 2–105?months, median follow-up 3.4?years), and 36 matched controls. Everolimus introduction was associated with a mean improvement in mGFR of 7?mL/min up to 1?year (p?=?.003), restricted to patients switched <1-year post-transplant and at tacrolimus trough levels >5?ng/mL. The differences between the everolimus group and controls in delta-mGFR from baseline to 1?year (7.3 vs 4.3?mL/min, p?=?.25) or 1-year to last follow-up (?0.8 vs ?0.2?mL/min/year, p?=?.71) were non-significant. Proportions with mGFR decline >3?mL/min/year were similar between groups (11% and 14%, p?=?1.00). Everolimus was stopped in three patients (8%), and acute rejection occurred in 17%. In conclusion, despite an early improvement in renal function after everolimus introduction, we found no evidence that everolimus halts the long-term mGFR decline compared to continued low-dose CNI therapy. Due to retrospective design, small sample size and heterogenous characteristics, definite conclusions require prospective studies.     

Autologous stem cell transplantation may be curative for patients with follicular lymphoma with early therapy failure without the need for immunotherapy

Objective/BackgroundPatients with follicular lymphoma (FL) with early therapy failure (ETF) within 2 years of frontline therapy have poor overall survival (OS). We recently reported the results of autologous stem cell transplantation (ASCT) in patients from the Grupo Español de Linfomas y Trasplantes de Médula Ósea (GELTAMO) registry treated with rituximab prior to ASCT and with ETF after first-line immunochemotherapy, leading to 81% 5-year OS since ASCT. We explored whether ASCT is also an effective option in the pre-rituximab era—that is, in patients treated in induction and rescued only with chemotherapy.MethodsETF was defined as relapse/progression within 2 years of starting first-line therapy. We identified two groups: the ETF cohort (n = 87) and the non-ETF cohort (n = 47 patients receiving ASCT but not experiencing ETF following first-line therapy).ResultsThere was a significant difference in 5-year progression-free survival between the ETF and non-ETF cohorts (43% vs. 57%, respectively; p = .048). Nevertheless, in patients with ETF with an interval from first relapse after primary treatment to ASCT of <1 year, no differences were observed in 5-year progression-free survival (48% vs. 66%, respectively; p = .44) or in 5-year OS (69% vs. 77%, p = .4). Patients in the ETF cohort transplanted in complete remission showed a plateau in the OS curves, at 56%, beyond 13.7 years of follow-up.ConclusionASCT may be a curative option for ETF in patients who respond to rescue chemotherapy, without the need for immunotherapy or other therapies, and should be considered as an early consolidation, especially in patients with difficult access to rituximab.     

Kidney biopsy in AA amyloidosis: impact of histopathology on prognosis

In AA amyloidosis, while kidney biopsy is widely considered for diagnosis by clinicians, there is no evidence that the detailed investigation of renal histopathology can be utilized for the prognosis and clinical outcomes. In this study, we aimed to obtain whether histopathologic findings in kidney biopsy of AA amyloidosis might have prognostic and clinical value.

This is a retrospective cohort study that included 38 patients who were diagnosed with AA amyloidosis by kidney biopsy between 2005 and 2013.The kidney biopsy specimens of patients were evaluated and graded for several characteristics of histopathological lesions and their relationship with renal outcomes.

Segmental amyloid deposition in the kidney biopsy was seen in 29%, global amyloid deposition in 71, diffuse involvement of glomeruli in 84.2%, focal involvement in 7%, glomerular enlargement in 53%, tubular atrophy in 75% and interstitial fibrosis in 78% of patients. Histopathologically, glomerular enlargement, interstitial fibrosis, tubular atrophy, interstitial inflammation and global amyloid deposition were significantly associated with lower estimated glomerular filtration rate (eGFR) (p?=?.02, p?p?=?.001, p?=?.009, p?=?.002, respectively) in univariate analysis. In multivariate analysis, tubular atrophy was the only predictor of eGFR (p?=?.019 B?=??20.573). In the follow-up at an average of 27?months, 18 patients developed end-stage renal disease (ESRD). Among them, global amyloid deposition was the only risk factor for the development of ESRD (p?=?.01, OR?=?18.750, %95?CI=?2.021–173.942).

This is the first study showing that the histopathological findings in kidney biopsy of AA amyloidosis might have a prognostic and clinical value for renal outcomes.     

Impact of involved free light chain (FLC) levels in patients achieving normal FLC ratio after initial therapy in light chain amyloidosis (AL)

Achievement of a normal FLC ratio (FLCr) following treatment indicates hematologic response and suggests better outcomes in light chain amyloidosis (AL). We examined if elevated involved free light chain (hiFLC) impacts outcomes in patients achieving normal FLCr. We retrospectively analyzed 345 AL patients who were diagnosed within a 10‐year period (2006‐2015) and had 2 consecutive normal FLCr values after 1st line treatment. Among these, patients with hiFLC at 1^st reading of normal FLCr (hiFLC1; n = 166; 48.1%) were compared to those who did not (n = 179; 51.9%). Patients with AL who have hiFLC1 after initial therapy had higher rates of multi‐organ involvement (63.3 vs 46.4%; P = .002) and patients in advanced Mayo stage (42.9 vs 32.2%; P = .04) at diagnosis. The median progression free survival [PFS; 38.2 (95%CI; 26.4, 55.4) vs 67.1 (95%CI; 55.8, 88) months; P = .0002] and overall survival [OS; 94.4 (95%CI; 78, 107.1) vs not reached (NR, 95%CI; 116.1, NR) months; P < .0001] were lower in those who had hiFLC1. A more stringent comparison for patients with 2 consecutive hiFLC (hIFLC2; n = 111; 32.2%) versus not (n = 2234; 67.8%) showed consistent results [PFS; 27.1 (95%CI; 23, 53.8) vs 63.3 (95%CI; 55.4, 77) months; P < .0001 and OS; 78 (95% CI; 54.6, 98.8) vs NR (95%CI; NR, NR); P < .0001]. This poor prognostic impact of hiFLC on survival was independent of serum creatinine, Mayo stage, negative immunofixation status and inclusion of transplant in initial therapy on multivariate analysis. Hence, persistent elevation of iFLC predicts poor prognosis even among patients achieving normal ratio after initial therapy in AL.     

Amyloid in bone marrow smears in systemic light-chain amyloidosis

We performed a prospective sensitivity analysis to detect amyloid in bone marrow (BM) smears stained with Congo red (CR) and according to Pappenheim of patients with systemic light-chain (AL) amyloidosis. Results were directly compared to routine BM histology and fat aspiration. We analysed 198 BM smears from patients with the diagnosis or suspicion of systemic AL amyloidosis. Ultimately, the diagnosis could be established for 168 patients. Amyloid was detected on BM smears with CR in 33% (56/168). All patients suspicious for amyloid on Pappenheim staining (n?=?39) showed substantial amyloid infiltration on CR. No patient without systemic AL amyloidosis stained positive. Sensitivity for routine BM histology was 57% (74/129) and for fat aspiration 96% (134/140). Patients with amyloid on BM smears had significantly more hepatic (42 vs. 9%, p?p?p?p?相似文献   

Long-term outcomes of the randomized controlled trial comparing 5-aminolaevulinic acid and Photofrin photodynamic therapy for Barrett’s oesophagus related neoplasia

Objective: Photodynamic therapy (PDT) was used as therapy for early neoplasia associated with Barrett’s oesophagus (BE). This is 5-year follow-up of patients enrolled into randomised controlled trial of 5-aminolaevulinic acid (ALA) vs. Photofrin PDT.

Methods: Biopsies were taken from original Barrett’s segment during endoscopic follow up using Seattle protocol. Endoscopic mucosal resection (EMR)?±?radiofrequency ablation (RFA) was preferred therapy in patients who failed PDT and/or had recurrent neoplasia.

Results: Fifty eight of 64 patients enrolled in the original trial were followed up including 31 patients treated with ALA PDT (17 patients with ≤6?cm, 14 patients with >6?cm segment of BE) and 27 treated with Photofrin PDT (14 patients with ≤6?cm, 13 patients with >6?cm BE). Initial success was achieved in 65% (20/31) ALA and 48% (13/27) Photofrin patients (p?=?.289). Thirty five percent patients (7/20) relapsed in ALA group and 54% (7/13) relapsed in Photofrin group (p?=?.472). At a median follow-up of 67 months, no significant difference was found in long-term complete reversal of intestinal metaplasia (CR-IM) and complete reversal of dysplasia (CR-D) between ALA and Photofrin groups (78% vs. 63%; p?=?.18; 90% vs. 76%; p?=?.26). Original length of BE did not alter long-term outcome. Four patients from each group progressed to invasive oesophageal adenocarcinoma. Initial success of ALA PDT was associated with significantly better likelihood of long-term remission (p?=?.03).

Conclusions: Initial response to PDT plays key role in long term outcome. RFA?±?EMR have, however, become preferred minimally invasive ablative therapy for BE-related neoplasia due to poor efficacy of PDT.     

Novel pathologic scoring tools predict end-stage kidney disease in light chain (AL) amyloidosis

Background and objectives: Light chain (AL) amyloidosis frequently involves the kidney, causing significant morbidity and mortality. A pathologic scoring system with prognostic utility has not been developed. We hypothesized that the extent of amyloid deposition and degree of scarring injury on kidney biopsy, could provide prognostic value, and aimed to develop pathologic scoring tools based on these features.

Methods: This is a case-control study of 39 patients treated for AL amyloidosis with biopsy-proven kidney involvement at a large academic medical center. Our novel scoring tools, composite scarring injury score (CSIS) and amyloid score (AS) were applied to each kidney biopsy. The primary outcome was progression to dialysis-dependent end-stage kidney disease (ESKD) using a 12-month landmark analysis.

Results: At 12?months, nine patients had progressed to ESKD. Patients with an AS ≥7.5 had a significantly higher cumulative incidence of ESKD than those with AS <7.5 (p?=?.04, 95% CI 0.13–0.64).

Conclusions: Using a 12-month landmark analysis, AS correlated with progression to ESKD. These data suggest that a kidney biopsy, in addition to providing diagnostic information, can be the basis for a pathologic scoring system with prognostic significance.     

At least partial hematological response after first cycle of treatment predicts organ response and long-term survival for patients with AL amyloidosis receiving bortezomib-based treatment

AL amyloidosis is a rare plasma cell dyscrasia characterized by multi-organ involvement and poor prognosis. We retrospectively evaluated the organ response (OR) and long-term survival of newly diagnosed AL amyloidosis patients who received first-line bortezomib-containing induction therapy, aiming to identify the clinical indication of a 50% reduction in the difference between involved and uninvolved free light chains (dFLC) after first cycle of treatment. Among the 89 patients included, 78.7% had cardiac involvement and 42.7% were diagnosed with 2004 Mayo stage III disease, while 75.3% of patients achieved a hematological response, including 37.1% with complete response and a median response time of 1 month. Cardiac and renal responses were observed in 44.3 and 53.1% of patients, respectively. Sixty-one (68.5%) patients achieved at least 50% reduction in dFLC after the first cycle of therapy. After a median follow-up duration of 12 months, the estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 61.3 and 61.7% respectively. At least 50% reduction in dFLC after the first cycle of therapy was predictive of achieving an OR (p = 0.002), as well as superior PFS (HR = 0.119; 95% CI = 0.045–0.313; p < 0.001) and OS (HR = 0.206; 95% CI = 0.078–0.541; p = 0.001). Additionally, the median PFS and OS were not reached for patients with rapid reduction of dFLC. These results demonstrated that early reduction of dFLC after the first cycle of treatment is predictive of achieving an OR and long-term survival in AL patients receiving bortezomib.