Publications by authors named "Erasmia Psimenou"

35 Publications

Consolidation with a short course of daratumumab in patients with AL amyloidosis or light chain deposition disease.

Amyloid 2021 Sep 1:1-8. Epub 2021 Sep 1.

Plasma Cell Dyscrasia Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

Daratumumab has major and rapid activity in AL amyloidosis with favourable toxicity. We used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain deposition disease (LCDD), who had not achieved a haematologic complete response (hemCR) after standard therapy with bortezomib, cyclophosphamide and dexamethasone (VCD). We evaluated minimal residual disease (MRD) and changes in the bone marrow (BM) microenvironment before and after consolidation using next generation flow cytometry (NGF). At the time of consolidation, 21 patients were in very good partial response (VGPR) and four in partial response (PR); all had detectable MRD. One month after consolidation completion, 8 patients (32%) achieved a hemCR, of whom 5 (20%) became also MRD negative. In the BM, we observed significant changes in B-cell precursors, naïve B-cells, T-cells, CD27+ NK & NKT cells, mast cells and erythroblasts. After a median follow-up of 25 months, none of the patients in hemCR has relapsed and all have achieved an organ response; a haematologic relapse occurred in 6/17 patients that did not achieve hemCR. In conclusion, consolidation with a short course of daratumumab can improve depth of response in patients with AL amyloidosis or LCDD and significantly affects BM environment.
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http://dx.doi.org/10.1080/13506129.2021.1971192DOI Listing
September 2021

Clinico-radiologic features and therapeutic strategies in tumefactive demyelination: a retrospective analysis of 50 consecutive cases.

Ther Adv Neurol Disord 2021 18;14:17562864211006503. Epub 2021 May 18.

Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Aims: Our goal was to expand the spectrum of clinico-radiologic characteristics and the possible therapeutic choices in patients with tumefactive demyelinating lesions (TDLs).

Methods: A retrospective analysis of 50 patients with at least one TDL was performed at an academic neurology center (2008-2020).

Results: Our cohort comprised mostly women (33/50) with a mean age of 38 years at TDL onset. The mean follow-up time was 76 months. The mean Expanded Disability Status Scale score at TDL onset and at the latest neurological evaluation was 3.7 and 2.3, respectively. We subcategorized the patients into seven groups based mainly on the clinical/radiological findings and disease course. Group A included patients presenting with a Marburg-like TDL ( = 4). Groups B and C comprised patients presenting with monophasic ( = 7) and recurrent TDLs ( = 12), respectively. Multiple sclerosis (MS) patients who subsequently developed TDL ( = 16) during the disease course were categorized as Group D. Group E comprised patients who initially presented with TDL and subsequently developed a classical relapsing-remitting MS without further evidence of TDL ( = 5). Groups F ( = 2) and G ( = 4) involved MS patients who developed TDL during drug initiation (natalizumab, fingolimod) and cessation (interferon, fingolimod), respectively. Regarding long-term treatments applied after corticosteroid administration in the acute phase, B-cell-directed therapies were shown to be highly effective especially in cases with recurrent TDLs. Cyclophosphamide was spared for more aggressive disease indicated by a poor response to corticosteroids and plasma exchange failure.

Conclusion: Tumefactive central nervous system demyelination is an heterogenous disease; its stratification into distinct groups according to different phenotypes can establish more efficient treatment strategies, thus improving clinical outcomes in the future.
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http://dx.doi.org/10.1177/17562864211006503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135218PMC
May 2021

Carfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients.

Blood Cancer J 2020 11 3;10(11):109. Epub 2020 Nov 3.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed and refractory myeloma (RRMM). Its use has been associated with cardiovascular toxicity but although recently a signal of clinically significant renal complications has also been identified, it is less extensively investigated. We analyzed data of 114 consecutive patients with RRMM who received CFZ-based regimens. Renal complications not related to MM progression were observed in 19 (17%) patients; thrombotic microangiopathy (TMA) was seen in 6 (5%) patients, albuminuria >1 gr/day in 7 patients (6%) and at least grade 3 acute kidney injury (AKI) which could not be otherwise explained in 6 patients (5%). A total of 15 patients discontinued CFZ and dosing was reinitiated at a lower level in one patient with AKI. Albuminuria was associated with focal segmental glomerulosclerosis in the renal biopsy (performed in a total of 6 patients). Renal complications during CFZ therapy are common, occur mostly early and are unpredictable. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ.
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http://dx.doi.org/10.1038/s41408-020-00381-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642386PMC
November 2020

Circulating Soluble Urokinase-Type Plasminogen Activator Receptor Levels Reflect Renal Function in Newly Diagnosed Patients with Multiple Myeloma Treated with Bortezomib-Based Induction.

J Clin Med 2020 Oct 3;9(10). Epub 2020 Oct 3.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.

(1) Background: Soluble urokinase-type plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney disease in different disease settings. The aim of this study was to investigate a possible link between suPAR circulating levels and renal impairment (RI) in newly diagnosed patients with symptomatic multiple myeloma (NDMM) before and after frontline therapy with bortezomib-based regimens. (2) Methods: We studied 47 NDMM patients (57% males, median age 69.5 years) before the administration of anti-myeloma treatment and at best response to bortezomib-based therapy. suPAR was measured in the serum of all patients and of 24 healthy matched controls, using an immuno-enzymatic assay (ViroGates, Denmark). (3) Results: suPAR levels were elevated in NDMM patients at diagnosis compared to healthy individuals ( < 0.001). suPAR levels strongly correlated with disease stage (-ANOVA < 0.001). suPAR levels both at diagnosis and at best response negatively correlated with estimated glomerular filtration rate (eGFR) values ( < 0.001). Interestingly, no significance changes in suPAR levels were observed at best response compared to baseline values ( = 0.31) among 18 responding patients with baseline eGFR < 50 mL/min/1.73 m. (4) Conclusions: SuPAR levels reflect renal function in NDMM patients treated with bortezomib-based induction. Responders may have elevated circulating suPAR levels, possibly reflecting persistent kidney damage, despite their renal response.
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http://dx.doi.org/10.3390/jcm9103201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600599PMC
October 2020

AChR-and MuSK-positive myasthenia gravis: Double trouble.

J Neuroimmunol 2020 11 3;348:577364. Epub 2020 Sep 3.

Renal Unit, Alexandra Hospital, Athens, Greece.

This is a report of an early onset AChR-and MuSK-positive myasthenia gravis. The double seropositivity was detected at the onset of the disease and persisted during 3.5 years follow-up despite the chronic immunotherapy and thymectomy. It is the second reported case of this rare immunological coexistence with sufficient follow-up and available clinical details. At the detection of double positive AChR and MuSK Abs, the treating physician often feels unsecure about the optimal treatment strategy and the long-term prognosis. The detailed clinical record and the long observation of these rare cases, are mandatory for best management in clinical practice.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577364DOI Listing
November 2020

Daratumumab-based therapy for patients with monoclonal gammopathy of renal significance.

Br J Haematol 2021 04 23;193(1):113-118. Epub 2020 Aug 23.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.
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http://dx.doi.org/10.1111/bjh.17052DOI Listing
April 2021

Timing and impact of a deep response in the outcome of patients with systemic light chain (AL) amyloidosis.

Amyloid 2021 Mar 27;28(1):3-11. Epub 2020 Jul 27.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC <20 mg/L and 15% dFLC <10 mg/L. Deep haematologic response at 1 month (either ≥VGPR or iFLC <20 mg/L or dFLC <10 mg/L), was associated with a high organ response rate. The survival of patients with ≥VGPR was significantly better than those with PR and NR at 1-month landmark ( < .001) but this benefit was mainly driven by those with iFLC <20 mg/L. The depth of haematologic response at 1 month was significant across all Mayo stages. At 3 months, 46% of the patients had not significantly improved the depth of their response but even patients that improved their response from an iFLC ≥20 mg/L at 1 month to iFLC <20 mg/L at 3 months still had inferior outcome to those with an early deep response. Thus, in patients with AL amyloidosis, a very rapid and deep response is crucial, especially for those at high risk, targeting very low FLC levels within the first month of therapy.
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http://dx.doi.org/10.1080/13506129.2020.1798224DOI Listing
March 2021

Autoimmune hemolytic anemia, demyelinating relapse, and AQP1 antibodies after alemtuzumab infusion.

Neurol Neuroimmunol Neuroinflamm 2020 05 2;7(3). Epub 2020 Apr 2.

From the 1st Department of Neurology (J.S.T., D.T., L.S. K.K.), Eginition Hospital, Medical School, National and Kapodistrian University of Athens (NKUA); Tzartos NeuroDiagnostics (J.S.T., C.S., M.D.); Blood Transfusion Department (S.V.), Aretaieion Hospital, Medical School, NKUA; Hematology Division (D.B.), Alexandra General Hospital; Department of Clinical Therapeutics (E.P.), Medical School, NKUA, and 2nd Department of Radiology (G.V.), Medical School, NKUA, Athens, Greece.

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http://dx.doi.org/10.1212/NXI.0000000000000711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136045PMC
May 2020

Primary treatment of light-chain amyloidosis with bortezomib, lenalidomide, and dexamethasone.

Blood Adv 2019 10;3(20):3002-3009

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

Bortezomib and dexamethasone with cyclophosphamide (CyBorD) or melphalan (BMDex) are commonly used primary treatments for light-chain (AL) amyloidosis, but limited data exist on bortezomib with immunomodulatory drug combinations. We report our experience with primary therapy with a bortezomib, lenalidomide, and dexamethasone (VRD) "light" regimen in 34 consecutive patients with AL amyloidosis. The majority (79%) had cardiac involvement, 15% and 23% were Mayo stage 3A and 3B, respectively, and 54% had renal involvement. After the first VRD cycle, 71% of patients achieved a hematologic response (44% at least very good partial response [VGPR]). On intent to treat, 11 (32%) achieved a complete response (of whom 5 of 11 were minimal residual disease [MRD] negative at 10-5), 17 (50%) a VGPR, and 2 (7%) a partial response. The 12-month survival was 73%. Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; nonhematologic toxicities included rash (grade 3/4 [16%]), infections (grade ≥3 [12%]), constipation (grade ≥3 [9%]), and peripheral neuropathy (grade 2 [20%]); 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide, 38% required bortezomib dose reduction, and 12% discontinued bortezomib. We compared VRD to CyBorD in 68 patients matched for Mayo stage and baseline difference between involved minus uninvolved serum free light chain levels, and observed a trend for deeper response at 3 and 6 months with VRD. In conclusion, VRD can be an active regimen for newly diagnosed patients with AL amyloidosis able to induce very deep hematologic responses at the expense of increased toxicity.
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http://dx.doi.org/10.1182/bloodadvances.2019000147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849948PMC
October 2019

Efficacy of lenalidomide as salvage therapy for patients with AL amyloidosis.

Amyloid 2018 Dec 20;25(4):234-241. Epub 2019 Jan 20.

a Department of Clinical Therapeutics , National and Kapodistrian University of Athens , Athens , Greece.

We retrospectively evaluated 55 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis. Their median age was 63 years; 72% had heart and 75% kidney involvement and 13% were on dialysis; while 20%, 46% and 34% had Mayo stage -1, -2 and -3 disease, respectively. Median time from start of primary therapy to lenalidomide was 15 months (range 2-100) and median number of prior therapies was 1 (range 1-4); 73% of the patients had prior bortezomib and 42% were bortezomib-refractory. On intent to treat, haematologic response rate was 51% (5.5% CRs, 20% VGPRs) and was 56% versus 40% for patients with and without prior bortezomib and 47% versus 62.5% for bortezomib refractory versus non-refractory patients (p = .351). Organ response was achieved by 16% of evaluable patients (22% renal, 7% liver and 3% cardiac); however, 10 (21%) patients progressed to dialysis. Median survival post lenalidomide was 25 months. Bortezomib-refractory patients had worse outcome (median survival of 10.5 versus 25 months for bortezomib-sensitive patients versus not reached for bortezomib-naive patients, p = .011). Median lenalidomide dose was 10 mg and no patient received the 25 mg dose; however, in 60% a dose reduction was required. Median duration of lenalidomide therapy was 7.2 months and 46% discontinued lenalidomide before completion of planned therapy, mainly due to toxicity (26%) or disease progression/no response (13%). We conclude that although lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, its toxicity in patients with AL amyloidosis is significant and doses should be adjusted for optimal tolerability.
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http://dx.doi.org/10.1080/13506129.2018.1540410DOI Listing
December 2018

Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis.

Blood 2018 04 31;131(14):1568-1575. Epub 2018 Jan 31.

Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Pavia, Italy; and.

Growth differentiation factor-15 (GDF-15) improves prognostication in patients with cardiovascular disorders in addition to conventional cardiac markers (N-terminal pro B-type natriuretic peptide [NT-proBNP], troponins [Tns]) and has shown prognostic value in patients with renal diseases. In patients with light chain (AL) amyloidosis, cardiac involvement is the major determinant of prognosis, and cardiac markers define prognosis, whereas biomarkers of renal involvement stratify renal risk. We explored the prognostic importance of serum level of GDF-15 in patients with AL amyloidosis in 2 independent cohorts. The prognostic value of GDF-15 level was initially evaluated in a cohort of 107 consecutive previously untreated patients with AL amyloidosis from Athens, Greece, and was then validated in a second cohort of 202 consecutive previously untreated patients from Pavia, Italy. High GDF-15 level was associated with a higher risk of early death and poor overall survival independently of NT-proBNP and high-sensitivity TnT (hsTnT) or hsTnI levels. At the 6-month landmark, reduction of GDF-15 level ≥25% was associated with improved outcome. GDF-15 level ≥4000 pg/mL was associated with a high risk of progression to dialysis, independently of renal risk defined by estimated glomerular filtration rate and proteinuria, in both cohorts; failure to reduce GDF-15 below this level was associated with increased risk at either the 3- or 6-month landmark, independently of the established renal response or progression criteria. In conclusion, GDF-15 has prognostic implications for different outcomes in patients with AL and adds prognostic information independent of that provided by cardiac and renal risk biomarkers.
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http://dx.doi.org/10.1182/blood-2017-12-819904DOI Listing
April 2018

Cardiac and renal complications of carfilzomib in patients with multiple myeloma.

Blood Adv 2017 Feb 27;1(7):449-454. Epub 2017 Feb 27.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Clinical trials with carfilzomib have indicated a low but reproducible incidence of cardiovascular and renal toxicities. Among 60 consecutive myeloma patients treated with carfilzomib-based regimens who were thoroughly evaluated for cardiovascular risk factors, 12% (95% confidence interval, 3.8%-20%) experienced a reversible reduction of left ventricular ejection fraction (LVEF) by ≥20%, an objective measure of cardiac dysfunction. The incidence of LVEF reduction was 5% at 3 months, 8% at 6 months, 10% at 12 months, and 12% at 15 months, whereas the respective carfilzomib discontinuation rate unrelated to toxicity was 17%, 35%, 41%, and 49%. The presence of any previously known cardiovascular disease was associated with an increased incidence of cardiac events (23.5% vs 7%; = .07), but there was no association with the dose of carfilzomib or the duration of infusion. Re-treatment with carfilzomib at lower doses was possible. Carfilzomib was commonly associated with a transient reduction of estimated glomerular filtration rate (eGFR) but also improved renal function in 55% of patients with baseline eGFR <60 mL/min/1.73 m. Further investigation is needed to elucidate the underlying mechanisms of carfilzomib-related cardiorenal toxicity.
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http://dx.doi.org/10.1182/bloodadvances.2016003269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738981PMC
February 2017

Renal outcomes in patients with AL amyloidosis: Prognostic factors, renal response and the impact of therapy.

Am J Hematol 2017 Jul 26;92(7):632-639. Epub 2017 May 26.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine.

A staging system for patients with renal AL amyloidosis, based on eGFR (<50 ml/min/1.73 m ) and proteinuria (≥5 g/day) at diagnosis, as well as criteria for renal progression (≥25% eGFR reduction) and response (≥30% reduction of proteinuria without renal progression) were recently proposed. We validated these criteria in a cohort of 125 patients with renal AL amyloidosis, mostly treated with bortezomib or lenalidomide. We confirmed the prognostic value of the renal staging system but also identified the limitations of renal progression criteria which are based only on eGFR reduction. We identified the ratio of 24h proteinuria to eGFR as a sensitive marker of renal risk which also accounts for changes in both proteinuria and eGFR: 24h proteinuria/eGFR ratio <30 (in mg/ml/min/1.73 m ) was associated with a 2-year progression to dialysis rate of 0% compared to 9% for a ratio of 31-99 and 35% for a ratio ≥100 (P < .001). In landmark analysis, patients who achieved a reduction of this ratio by at least 25% or ≤100 (if initially >100) at 3 months had a 2-year progression to dialysis of 0% vs 24% for patients who either did not reduce to or still had a ratio >100 (P = .001); similar results were obtained by applying the same criteria at 6 months; thus, the evaluation of treatment effect on renal function may be identified early. Furthermore, primary bortezomib-based therapy was more effective than lenalidomide-based therapy, in terms of renal outcomes, especially in patients at intermediate renal risk, but without affecting overall survival.
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http://dx.doi.org/10.1002/ajh.24738DOI Listing
July 2017

Hematologic and renal improvement of monoclonal immunoglobulin deposition disease after treatment with bortezomib-based regimens.

Leuk Lymphoma 2017 08 14;58(8):1832-1839. Epub 2016 Dec 14.

a Department of Clinical Therapeutics , Alexandra General Hospital, National and Kapodistrian University of Athens, School of Medicine , Athens , Greece.

Monoclonal immunoglobulin deposition disease (MIDD) is characterized by non-organized immunoglobulin-fragments along renal basement membranes with subsequent organ deterioration. Treatment is directed against the immunoglobulin-producing clone. We treated 18 MIDD patients with bortezomib-based regimens (12 received bortezomib-dexamethasone, 6 bortezomib-dexamethasone with cyclophosphamide). Eleven (61%) patients achieved a hematologic response, but only 6 (33.3%) reached to a complete (CR) or very good partial response (VGPR). Regarding renal outcomes 77.8 and 55.6% had ≥30 and ≥50% reduction of proteinuria, respectively, but 33.3% ended up in end-stage renal disease (ESRD). Among patients with CR or VGPR, median eGFR improvement was 7.7 ml/min/1.73 m and none progressed to ESRD, but no significant renal recovery was observed in patients achieving a partial response or less, with 50% progressing to dialysis. Pretreatment eGFR seems to influence renal prognosis. Bortezomib-based treatment is considered an effective approach in MIDD and reaching to a deep hematologic response (≥VGPR) conditionally controls further renal declining.
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http://dx.doi.org/10.1080/10428194.2016.1267349DOI Listing
August 2017

Clinical and prognostic significance of serum levels of von Willebrand factor and ADAMTS-13 antigens in AL amyloidosis.

Blood 2016 07 10;128(3):405-9. Epub 2016 May 10.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece;

Cardiac dysfunction determines prognosis in amyloid light-chain (AL) amyloidosis. The heart is the central organ of the vascular system in which endothelium function is critical for the circulatory homeostasis, but there are limited data on endothelial function in AL amyloidosis. von Willebrand factor (VWF) has been considered as a marker of endothelial activation and dysfunction, whereas a disintegrin and metalloproteinase with thrombospondin type-1 repeats 13 (ADAMTS-13) cleaves VWF multimers, but both have been associated with prognosis in cardiovascular disease. We measured the serum levels of VWF (VWF:Ag) and ADAMTS-13 antigens in 111 newly diagnosed patients with AL amyloidosis. The levels of VWF:Ag were significantly higher than in healthy controls; 76% of patients with AL had VWF:Ag levels higher than the upper levels of controls. There was no significant association of VWF:Ag levels with patterns of organ involvement, free light-chain levels, the levels of cardiac biomarkers, or renal dysfunction but correlated with low systolic blood pressure. VWF:Ag levels ≥230.0 U/dL were associated with higher probability of early death and poor survival independently of cardiac biomarkers and low systolic blood pressure (SBP). Moreover, among patients with Mayo stage III or stage IIIB (that is stage III with N-terminal pro-brain natriuretic peptide [NTproBNP] >8500 pg/mL) disease, VWF:Ag identified subgroups of patients with very poor outcome. Low ADAMTS-13 levels correlated with high levels of NTproBNP but had no independent prognostic significance. In conclusion, high VWF:Ag levels, probably representing endothelial dysfunction, are associated with prognosis in patients with AL amyloidosis, independently of other features of the disease or cardiac biomarkers.
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http://dx.doi.org/10.1182/blood-2016-02-702696DOI Listing
July 2016

Bortezomib-based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis.

Am J Hematol 2016 May 4;91(5):499-502. Epub 2016 Apr 4.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Renal failure (RF) is a common and severe complication of symptomatic myeloma, associated with significant morbidity and mortality. Such patients are commonly excluded from clinical trials. Bortezomib/dexamethasone (VD)-based regimens are the backbone of the treatment of newly diagnosed MM patients who present with severe RF even those requiring dialysis. We analyzed the outcomes of 83 consecutive bortezomib-treated patients with severe RF (eGFR < 30 ml/min/1.73 m(2) ), of which 31 (37%) required dialysis. By IMWG renal response criteria, 54 (65%) patients achieved at least MRrenal, including CRrenal in 35% and PRrenal in 12%. Triplet combinations (i.e., VD plus a third agent) versus VD alone were associated with higher rates of renal responses (72 vs. 50%; P = 0.06). Fifteen of the 31 (48%) patients became dialysis independent within a median of 217 days (range 11-724). Triplets were associated with a higher probability of dialysis discontinuation (57 vs. 35%). Serum free light chain (sFLC) level ≥11,550 mg/L was associated with lower rates of major renal response, longer time to major renal response, lower probability, and longer time to dialysis discontinuation. Rapid myeloma response (≥PR within the first month) was also associated with higher rates of renal response. Patients who became dialysis-independent had longer survival than those remaining on dialysis. In conclusion, VD-based triplets are associated with a significant probability of renal response and dialysis discontinuation, improving the survival of patients who became dialysis independent. Rapid disease response is important for renal recovery and sFLCs are predictive of the probability and of the time required for renal response.
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http://dx.doi.org/10.1002/ajh.24335DOI Listing
May 2016

Long-term outcomes of primary systemic light chain (AL) amyloidosis in patients treated upfront with bortezomib or lenalidomide and the importance of risk adapted strategies.

Am J Hematol 2015 Apr 9;90(4):E60-5. Epub 2015 Mar 9.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Bortezomib and lenalidomide are increasingly used in patients with AL amyloidosis, but long term data on their use as primary therapy in AL amyloidosis are lacking while early mortality remains significant. Thus, we analyzed the long term outcomes of 85 consecutive unselected patients, which received primary therapy with bortezomib or lenalidomide and we prospectively evaluated a risk adapted strategy based on bortezomib/dexamethasone to reduce early mortality. Twenty-six patients received full-dose bortezomib/dexamethasone, 36 patients lenalidomide with oral cyclophosphamide and low-dose dexamethasone and 23 patients received bortezomib/dexamethasone at a dose and schedule adjusted to the risk of early death. On intent to treat, 67% of patients achieved a hematologic response (24% hemCRs) and 34% an organ response; both were more frequent with bortezomib. An early death occurred in 20%: in 36% of those treated with full-dose bortezomib/dexamethasone, in 22% of lenalidomide-treated patients but only in 4.5% of patients treated with risk-adapted bortezomib/dexamethasone. Activity of full vs. adjusted dose bortezomib/dexamethasone was similar; twice weekly vs. weekly administration of bortezomib also had similar activity. After a median follow up of 57 months, median survival is 47 months and is similar for patients treated with bortezomib vs. lenalidomide-based regimens. However, risk adjusted-bortezomib/dexamethasone was associated with improved 1-year survival vs. full-dose bortezomib/dexamethasone or lenalidomide-based therapy (81% vs. 56% vs. 53%, respectively). In conclusion, risk-adapted bortezomib/dexamethasone may reduce early mortality and preserve activity while long term follow up indicates that remissions obtained with lenalidomide or bortezomib may be durable, even without consolidation with alkylators.
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http://dx.doi.org/10.1002/ajh.23936DOI Listing
April 2015

AChR-myasthenia gravis switching to double-seropositive several years after the onset.

J Neuroimmunol 2014 Feb 22;267(1-2):111-2. Epub 2013 Dec 22.

Department of Biochemistry, Hellenic Pasteur Institute, Greece; Tzartos NeuroDiagnostics, Athens, Greece.

We report an early onset AChR-myasthenia gravis (MG) with biphasic clinical course. The clinical "switch" from AChR-MG to MuSK-MG emerged 16 years after the onset and 11 years after thymectomy. MuSK antibodies were detected only by cell-based assay and only upon clinical "switch", while AChR antibodies remained positive and at high titers during the whole disease course. Although the occurrence of AChR antibodies and MuSK antibodies in the same individual is rare, the re-assessment of the antibody status, using all available assays, is advisable when there is clinical indication.
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http://dx.doi.org/10.1016/j.jneuroim.2013.12.012DOI Listing
February 2014

Renal impairment is not an independent adverse prognostic factor in patients with multiple myeloma treated upfront with novel agent-based regimens.

Leuk Lymphoma 2011 Dec;52(12):2299-303

Department of Clinical Therapeutics, University of Athens, School of Medicine, Alexandra Hospital, Athens, Greece.

Abstract Renal impairment (RI) is a common presenting complication of multiple myeloma associated with significant morbidity and early mortality, while it has been associated with inferior survival in patients treated with conventional regimens. We assessed the impact of RI in 203 unselected consecutive patients treated upfront with novel agents (thalidomide, lenalidomide, bortezomib). RI was assessed by the estimated glomerular filtration rate (eGFR). RI (eGFR <60 mL/min) was present in 93 (45.8%) of patients at diagnosis and was associated with advanced age, advanced International Staging System (ISS) stage, poorer performance status, hypercalcemia, urine Bence-Jones proteinuria, anemia and thrombocytopenia. Myeloma response rates were similar for patients with or without RI. In univariate analysis RI was associated with shorter survival and a higher rate of early death (7% vs. 3.5%); however, when adjusted for other prognostic factors, RI was not independently associated with survival. In conclusion, in unselected newly diagnosed patients treated with novel agent-based therapies, RI is not independently associated with inferior survival, probably due to the significant activity of novel agents even in the context of RI.
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http://dx.doi.org/10.3109/10428194.2011.597906DOI Listing
December 2011

Reversibility of renal failure in newly diagnosed patients with multiple myeloma and the role of novel agents.

Leuk Res 2010 Oct 26;34(10):1395-7. Epub 2010 May 26.

Department of Clinical Therapeutics, University of Athens School of Medicine, 80 Vas Sofias, Athens 11528, Greece.

The purpose of this analysis was to assess the effect of novel agent-based regimens on the improvement of renal impairment (RI) in newly diagnosed patients with multiple myeloma. Ninety-six consecutive patients with RI received conventional chemotherapy (CC)-based regimens (n=32), IMiDs-based regimens (n=47) or bortezomib-based regimens (n=17) as frontline therapy. Improvement of RI was more frequent in patients treated with novel agents (79% in IMiD- and 94% in bortezomib-treated groups versus 59% in CC-treated group; p=0.02). Bortezomib-based regimens and CrCl>30 ml/min at baseline independently correlated with a higher probability of at least renal partial response (PRrenal) and with a shorter time to PRrenal or better. Thus bortezomib-based regimens may be the preferred treatment for newly diagnosed myeloma patients with RI.
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http://dx.doi.org/10.1016/j.leukres.2010.04.024DOI Listing
October 2010

Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment.

Eur J Haematol 2010 Jul 20;85(1):1-5. Epub 2010 Feb 20.

Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece.

Objectives: Lenalidomide and dexamethasone (LenDex) is an active regimen for relapsed/refractory multiple myeloma (MM). However, there is limited data for the effect of LenDex on renal impairment (RI) and on renal reversibility.

Patients & Methods: Fifty consecutive patients with relapsed/refractory MM received LenDex in 28-d cycles. Median lines of previous therapies were 2 (range: 1-6). Lenalidomide was administered on days 1-21 according to creatinine clearance (CrCl), while dexamethasone was given at a dose of 40 mg on days 1-4 and 15-18 for the first four cycles and only on days 1-4 thereafter.

Results: Twelve patients (24%) had RI at baseline, defined as CrCl < 50 mL/min. Most patients were pretreated with either thalidomide or bortezomib and > 50% of them were refractory to both drugs. At least partial response was documented in 60.5% and 58% of patients with and without RI. Median progression-free survival (PFS) and overall survival (OS) for all patients was 9 and 16 months, respectively. RI was not associated with an inferior PFS or OS. There were no differences in the incidence of adverse events among patients with and without RI. Three of 12 patients with RI (25%) achieved complete renal response and two (16%) achieved minor renal response with LenDex.

Conclusions: We conclude that LenDex is an active treatment even in heavily pretreated MM. With dosing of lenalidomide according to renal function, LenDex can be administered to patients with RI (who may not have other treatment options) without excessive toxicity. Furthermore, LenDex may improve the renal function in approximately 40% of patients with RI.
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http://dx.doi.org/10.1111/j.1600-0609.2010.01432.xDOI Listing
July 2010

Fibroblast growth factor 23 (FGF23) and the kidney.

Int J Artif Organs 2009 Apr;32(4):232-9

Renal Unit, Alexandra Hospital, Athens, Greece.

Phosphate homeostasis in humans is a complex phenomenon involving the interplay of several different organs and circulating hormones. Among the latter, parathyroid hormone (PTh), and vitamin D3 (Vit D3) were thought to be the main regulators of serum phosphate concentration since they mediated the intestinal, renal and bone responses that follow fluctuations in serum phosphate levels. The study of three rare disorders - tumor-induced osteomalacia (TIo), autosomal dominant hypophosphatemic rickets (ADhr) and X-linked hypophosphatemic rickets (XLh) - has offered a completely new insight into phosphate metabolism by unraveling the role of a group of peptides that can directly affect serum phosphate concentration by increasing urinary phosphate excretion. fibroblast growth factor-23 (fGf-23) is the most extensively studied ''phosphatonin''. The production, mechanism of action, effects in various target tissues, and its role in common clinical disorders are the focus of this review.
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http://dx.doi.org/10.1177/039139880903200407DOI Listing
April 2009

Periodic therapeutic plasma exchange in patients with moderate to severe chronic myasthenia gravis non-responsive to immunosuppressive agents: an eight year follow-up.

Ther Apher Dial 2009 Jun;13(3):174-8

Department of Neurology, Aeginition Hospital, University of Athens, 72-74 Vass. Sofias Avenue, Athens, Greece.

Few patients with moderate or severe myasthenia gravis (MG) do not respond to immunosuppressive treatment. We present our experience with periodic therapeutic plasma exchange (TPE), in 11 patients with MG resistant to intravenous immunoglobulin (IVIg) therapy, who had frequent relapses even whilst on high doses of immunosuppressive drugs, over a period of 8 years. All patients underwent TPE until control of their symptoms was achieved, and afterwards TPE sessions were continued periodically in an attempt to achieve remission of the disease, without immunosuppressant therapy. Two of the patients were progressively weaned off immunosuppressive agents, as well as TPE, and they are now symptom free. The other nine patients are still under a periodic TPE regime. Seven of them were weaned off all medications and required an average of 3.7 TPE sessions per year during the last 5 years. In the other two patients, those with the most severe form of the disease, the immunosuppressant dosage has been decreased and a TPE session every 2-3 weeks is required in order to control their symptoms. Through all these years TPE has been well tolerated and only minor side-effects were observed in two patients. Finally, during this 8 year follow-up period, nine of the patients treated with periodic TPE have been in good control of their symptoms over the last 5 years, and the other two patients live a normal life without any treatment in the last 3 years. Our results suggest that periodic TPE is safe and effective in the control of symptoms in patients with moderate to severe MG who do not respond to immunosuppressive therapies.
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http://dx.doi.org/10.1111/j.1744-9987.2009.00684.xDOI Listing
June 2009

Rapamycin for focal segmental glomerulosclerosis: a report of 3 cases.

Am J Kidney Dis 2009 Aug 21;54(2):340-4. Epub 2009 Mar 21.

Renal Unit, Alexandra Hospital, Athens, Greece.

Corticosteroids and/or cyclosporine constitute the present therapeutic approach for patients with focal segmental glomerulosclerosis (FSGS). The high incidence of side effects for the former and risk of nephrotoxicity combined with the high relapse rate after discontinuation for the latter render their use problematic. Results concerning the role of rapamycin in the treatment of patients with FSGS are conflicting. We describe results for 3 patients treated with a combination of low-dose steroids and rapamycin for FSGS, focusing on the importance of maintaining low drug (rapamycin) levels by using a twice-daily regimen.
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http://dx.doi.org/10.1053/j.ajkd.2008.12.024DOI Listing
August 2009

Treatment of patients with multiple myeloma complicated by renal failure with bortezomib-based regimens.

Leuk Lymphoma 2008 May;49(5):890-5

Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, Sophias, Greece.

Unlabelled: Renal failure is a common feature of multiple myeloma and a major management problem. However there is limited data regarding the reversibility of renal failure, the kinetics of serum creatinine and the safety of novel agents such as bortezomib when administered to newly diagnosed or relapsed/refractory patients with renal failure.

Patients And Methods: We evaluated 20 consecutive patients with newly diagnosed or relapsed/refractory multiple myeloma and renal failure, defined as a serum creatinine >or= 2 mg/dl. All patients received bortezomib with dexamethasone or in combination with other agents (thalidomide, doxorubicin or melphalan).

Results: Reversal of renal failure was documented in 40% of all patients and the median time to reversal was 17 days. Moreover 10 patients (50%) had 50% decrease in serum creatinine and the median time to decrease was 35 days. Some decrease of creatinine was documented in 85% of patients. The objective response rate was 65%. Toxicities were similar to those seen in myeloma patients without renal failure.

Conclusions: Bortezomib based regimens can be administered to myeloma patients with renal impairment and their toxicity and efficacy are similar to those observed in patients without renal impairment. Moreover, bortezomib-based regimens induce improvement of serum creatinine in most patients and reversal of renal failure in approximately one-third.
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http://dx.doi.org/10.1080/10428190801930506DOI Listing
May 2008

Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone.

Haematologica 2007 Oct;92(10):1351-8

Department of Clinical Therapeutics, Alexandra Hospital, University of Athens, School of Medicine, Athens, Greece.

Background And Objectives: High-dose melphalan and autologous stem cell transplantation is currently the treatment of choice for selected patients with AL amyloidosis; however, new treatments are needed for patients who are ineligible for or relapse after this procedure. Bortezomib is a proteasome inhibitor with proven activity in multiple myeloma, and the addition of dexamethasone results in superior outcome. We evaluated the activity and feasibility of the combination of bortezomib and dexamethasone (BD) in patients with AL amyloidosis.

Design And Methods: Consecutive patients with histologically proven, symptomatic AL amyloidosis were treated with BD.

Results: Eighteen patients, including seven who had relapsed or progressed after previous therapies were treated with BD. Eleven (61%) patients had two or more organs involved; kidneys and heart were affected in 14 and 15 patients, respectively. The majority of patients had impaired performance status and high brain natriuretic peptide values; serum creatinine was elevated in six patients. Among evaluable patients, 94% had a hematologic response and 44% a hematologic complete response, including all five patients who had not responded to prior high dose dexamethasone-based treatment and one patient under dialysis. Five patients (28%) had a response in at least one affected organ. Hematologic responses were rapid (median 0.9 months) and median time to organ response was 4 months. Neurotoxicity, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were manageable although necessitated dose adjustment or treatment discontinuation in 11 patients.

Interpretation And Conclusions: The combination of BD is feasible in patients with AL amyloidosis. Patients achieve a rapid hematologic response and toxicity can be managed with close follow-up and appropriate dose adjustment. This treatment may be a valid option for patients with severe heart or kidney impairment.
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http://dx.doi.org/10.3324/haematol.11325DOI Listing
October 2007

Late recurrent urinary tract infections may produce renal allograft scarring even in the absence of symptoms or vesicoureteric reflux.

Transplantation 2007 Aug;84(3):351-5

Department of Nephrology and Transplantation, Royal Free Hospital, London, United Kingdom.

Background: The significance of late urinary tract infections (UTIs) after renal transplantation and their association with scarring and graft dysfunction remains controversial. We sought to define the prevalence of renal scarring in allograft recipients with a history of late recurrent UTIs, to determine whether the presence of vesicoureteric reflux (VUR) confers an increased risk of scarring and to establish whether scarring correlates with graft dysfunction.

Methods: Among 307 renal allograft recipients, we identified 56 (18%) with late recurrent UTIs (> or =3/year). A total of 32 patients had undergone further investigation by both 2,3 dimercapto-succinic acid single-photon emission computed tomography (99mTc-DMSA SPECT) scan and micturating cystourethrogram (MCUG).

Results: Of the 32 patients, 24 (75%) had scars on 99mTc-DMSA SPECT and 15 (47%) had reflux on MCUG. Thirteen of these 15 patients with reflux (87%) had scars, although there was no significant correlation between number of scars and degree of reflux. Eleven of 17 patients (65%) with UTIs but without VUR had scars, as did 12 of 14 (86%) with previous graft pyelonephritis. The pattern of scarring (typically multiple focal cortical defects) suggested infection as the cause. This pattern was not seen in a contemporary cohort with vascular occlusions and was rarely seen in patients with chronic allograft nephropathy. Scarring was not associated with inferior graft survival (median follow-up, 15 years).

Conclusions: In patients with late UTIs, renal scarring is a frequent finding. Scarring may occur even in asymptomatic patients without VUR. The lack of an effect on graft survival may reflect successful intervention with prophylactic antibiotics and surveillance urine cultures. Late recurrent UTIs may be damaging to renal allografts, even in the absence of reflux.
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http://dx.doi.org/10.1097/01.tp.0000275377.09660.faDOI Listing
August 2007

Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-containing regimens and the impact of novel agents.

Haematologica 2007 Apr;92(4):546-9

Department of Clinical Therapeutics, Alexandra Hospital, University of Athens, School of Medicine, Athens, Greece.

The impact of high dose dexamethasone containing regimens with or without the novel agents thalidomide and bortezomib on the reversal of renal failure (RF) was evaluated in 41 consecutive newly diagnosed patients with multiple myeloma (MM) treated in a single institution. RF was reversed in 73% of all patients within a median of 1.9 months. In patients treated with dexamethasone and novel agents (thalidomide and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months. Severe RF and significant Bence Jones proteinuria were associated with a lower probability of RF reversal. Patients who responded to treatment achieved RF reversal more often than in those who did not (85% versus 56%, p=0.046). In conclusion, RF is reversible in the majority of newly diagnosed MM patients treated with high-dose dexamethasone containing regimens. The addition of novel agents induces a more rapid RF reversal.
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http://dx.doi.org/10.3324/haematol.10759DOI Listing
April 2007
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