Publications by authors named "Stefan O Schönland"

64 Publications

Clarification on the definition of complete haematologic response in light-chain (AL) amyloidosis.

Amyloid 2021 Jan 7:1-2. Epub 2021 Jan 7.

Amyloidosis Research and Treatment Center, Foundation "Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo", Department of Molecular Medicine, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1080/13506129.2020.1868810DOI Listing
January 2021

Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data.

Ann Hematol 2020 Dec 3. Epub 2020 Dec 3.

Department of Internal Medicine V (Hematology/Oncology/Rheumatology), Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). We evaluated 80 seropositive patients transplanted consecutively between March 2018 and March 2019 who received letermovir (LET) prophylaxis from engraftment until day +100 and retrospectively compared them with 80 patients without LET allografted between January 2017 and March 2018. The primary endpoint of this study was the cumulative incidence (CI) of clinically significant CMV infection (CS-CMVi) defined as CMV reactivation demanding preemptive treatment or CMV disease. With 14% CI of CS-CMVi at day +100 (11 events) was significantly lower in the LET cohort when compared to the control group (33 events, 41%; HR 0.29; p < 0.001). Whereas therapy with foscarnet could be completely avoided in the LET group, 7 out of 80 patients in the control cohort received foscarnet, resulting in 151 extra in-patient days for foscarnet administration (p = 0.002). One-year overall survival was 72% in the control arm vs 84% in the LET arm (HR 0.75 [95%CI 0.43-1.30]; p < 0.306). This study confirms efficacy and safety of LET for prophylaxis of CS-CMVi after alloHCT in a real-world setting, resulting in a significant patient benefit by reducing hospitalization needs and exposure to potentially toxic antiviral drugs for treatment of CMV reactivation.
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http://dx.doi.org/10.1007/s00277-020-04362-2DOI Listing
December 2020

Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis.

J Clin Oncol 2020 10 30;38(28):3252-3260. Epub 2020 Jul 30.

Amyloidosis Research and Treatment Center "Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo," Pavia, Italy.

Purpose: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex).

Methods: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016.

Results: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% 52%; = .002). Higher rates of very good partial or complete response rates (64% 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed.

Conclusion: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.
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http://dx.doi.org/10.1200/JCO.20.01285DOI Listing
October 2020

Prognosis and Staging of AL Amyloidosis.

Acta Haematol 2020 22;143(4):388-400. Epub 2020 Jun 22.

Department of Internal Medicine V, Division of Hematology/Oncology, Heidelberg University Hospital, Heidelberg, Germany,

The treatment options for systemic light chain amyloidosis (AL) are currently widening in an unprecedented way, brought about by an expanding arsenal of anti-myeloma therapy as well as by novel approaches to target toxic light chains and, most recently, deposited amyloid directly. In this context, accurate estimates of prognosis in AL, which allow for reliable patient advice and for example comparison of different therapies, are particularly important to clinicians. Some biomarkers and especially the genetic background of the underlying clonal disease as evaluated by interphase fluorescence in situ hybridization even have predictive value, enabling an appropriate treatment selection. Derived from the most frequently involved organs in AL, heart and kidney, this review focuses on overall survival and renal survival. A comprehensive overview and summary of reported prognostic factors and biomarkers in AL is given and the most important and validated factors are highlighted. Finally, established staging systems in AL as well as validated and perspective response criteria are presented.
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http://dx.doi.org/10.1159/000508287DOI Listing
September 2020

Pomalidomide and dexamethasone grant rapid haematologic responses in patients with relapsed and refractory AL amyloidosis: a European retrospective series of 153 patients.

Amyloid 2020 Dec 25;27(4):231-236. Epub 2020 May 25.

Medical Department V, Amyloidosis Centrum, University Hospital, University of Heidelberg, Heidelberg, Germany.

Pomalidomide demonstrated activity in the treatment of AL amyloidosis in three phase II clinical trials. We evaluated the safety and efficacy of 28-day cycles of pomalidomide and dexamethasone in 153 previously treated patients with systemic AL amyloidosis. Ninety-nine (65%) were refractory to the last line of therapy and 54 (35%) had relapsed. The median number of previous lines of therapy was 3 (range: 2-7): 143 patients (93%) previously received bortezomib, 124 (81%) lenalidomide, 114 (75%) oral melphalan, and 37 (24%) underwent autologous stem cell transplant. At the completion of cycle 6, 68 (44%) patients obtained at least partial haematologic response, with 5 complete responses (CR, 3%), 35 very good partial responses (VGPR, 23%). Haematologic response resulted in improved overall survival (median survival 50 vs. 27 months,  = .033) in a 6 months landmark analysis. Obtaining at least partial response was also associated with a significant improvement of the progression-free survival (median PFS 37 vs. 18 months,  < .001). Pomalidomide is an effective treatment for heavily pre-treated patients with AL amyloidosis. Haematologic responses are associated with an overall survival advantage.
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http://dx.doi.org/10.1080/13506129.2020.1767566DOI Listing
December 2020

Magnetization transfer ratio quantifies polyneuropathy in hereditary transthyretin amyloidosis.

Ann Clin Transl Neurol 2020 05 25;7(5):799-807. Epub 2020 Apr 25.

Amyloidosis Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.

Objective: To quantify peripheral nerve lesions in symptomatic and asymptomatic hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PNP) by analyzing the magnetization transfer ratio (MTR) of the sciatic nerve, and to test its potential as a novel biomarker for macromolecular changes.

Methods: Twenty-five patients with symptomatic ATTRv-PNP, 30 asymptomatic carriers of the mutant transthyretin gene (mutTTR), and 20 age-/sex-matched healthy controls prospectively underwent magnetization transfer contrast imaging at 3 Tesla. Two axial three-dimensional gradient echo sequences with and without an off-resonance saturation rapid frequency pulse were conducted at the right distal thigh. Sciatic nerve regions of interest were manually drawn on 10 consecutive axial slices in the images without off-resonance saturation, and then transferred to the corresponding slices that were generated by the sequence with the off-resonance saturation pulse. Subsequently, the MTR and cross-sectional area (CSA) of the sciatic nerve were evaluated. Detailed neurologic and electrophysiologic examinations were conducted in all ATTRv-PNP patients and mutTTR-carriers.

Results: Sciatic nerve MTR and CSA reliably differentiated between ATTRv-PNP, mutTTR-carriers, and controls. MTR was lower in ATTRv-PNP (26.4 ± 0.7; P < 0.0001) and in mutTTR-carriers (32.6 ± 0.8; P = 0.0005) versus controls (39.4 ± 2.1), and was also lower in ATTRv-PNP versus mutTTR-carriers (P = 0.0009). MTR correlated negatively with the NIS-LL and positively with CMAPs and SNAPs. CSA was higher in ATTRv-PNP (34.3 ± 1.7 mm ) versus mutTTR-carriers (26.0 ± 1.1 mm ; P = 0.0005) and versus controls (20.4 ± 1.2 mm ; P < 0.0001). CSA was also higher in mutTTR-carriers versus controls.

Interpretation: MTR is a novel imaging marker that can quantify macromolecular changes in ATTRv-PNP and differentiate between symptomatic ATTRv-PNP and asymptomatic mutTTR-carriers and correlates with electrophysiology.
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http://dx.doi.org/10.1002/acn3.51049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261747PMC
May 2020

Daratumumab for systemic AL amyloidosis: prognostic factors and adverse outcome with nephrotic-range albuminuria.

Blood 2020 04;135(18):1517-1530

Division of Hematology/Oncology, Department of Internal Medicine V, and.

Daratumumab has shown promising first results in systemic amyloid light-chain (AL) amyloidosis. We analyzed a consecutive series of 168 patients with advanced AL receiving either daratumumab/dexamethasone (DD, n = 106) or daratumumab/bortezomib/dexamethasone (DVD, n = 62). DD achieved a remission rate (RR) of 64% and a very good hematologic remission (VGHR) rate of 48% after 3 months. Median hematologic event-free survival (hemEFS) was 11.8 months and median overall survival (OS) was 25.6 months. DVD achieved a 66% RR and a 55% VGHR rate. Median hemEFS was 19.1 months and median OS had not been reached. Cardiac organ responses were noted in 22% with DD and 26% with DVD after 6 months. Infectious complications were common (Common Terminology Criteria [CTC] grade 3/4: DD 16%, DVD 18%) and likely related to a high rate of lymphocytopenia (CTC grade 3/4: DD 20%, DVD 17%). On univariable analysis, hyperdiploidy and gain 1q21 conferred an adverse factor for OS and hemEFS with DD, whereas translocation t(11;14) was associated with a better hemEFS. N-terminal prohormone of brain natriuretic peptide >8500 ng/L could not be overcome for survival with each regimen. Multivariable Cox regression analysis revealed plasma cell dyscrasia (difference between serum free light chains [dFLC]) >180 mg/L as an overall strong negative prognostic factor. Additionally, nephrotic-range albuminuria with an albumin-to-creatinine-ratio (ACR) >220 mg/mmol was a significantly adverse factor for hemEFS (hazard ratio, 2.1 and 3.1) with DD and DVD. Daratumumab salvage therapy produced good results and remission rates challenging any therapy in advanced AL. Outcome is adversely influenced by the activity of the underlying plasma cell dyscrasia (dFLC) and nephrotic-range albuminuria (ACR).
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http://dx.doi.org/10.1182/blood.2019003633DOI Listing
April 2020

A novel risk score to predict survival in advanced heart failure due to cardiac amyloidosis.

Clin Res Cardiol 2020 Jun 19;109(6):700-713. Epub 2019 Oct 19.

Division of Cardiology, Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Background: Cardiac amyloidosis, caused by deposition of immunoglobulin light chains (AL) or transthyretin (ATTR), carries a poor prognosis. Established risk scores for amyloidosis may not predict outcomes in those patients who develop advanced heart failure and who are potential candidates for heart transplantation. Here, we aimed to identify predictive parameters for patients with severe heart failure due to amyloidosis.

Methods: Out of > 1000 patients with cardiac amyloidosis (AL or ATTR) admitted to our centre between September 1998 and January 2016, a cohort of 120 patients with a complete cardiac assessment at diagnosis, including right heart catheterization, echocardiography and biomarkers, was analysed retrospectively in this study. Primary endpoint was all-cause mortality. We performed univariate and multivariate Cox regression analysis, generated risk scores to predict outcomes in AL and ATTR amyloidosis and compared those to established risk models for amyloidosis.

Results: In the Cox multivariate model, high-sensitivity troponin T (hsTnT; hazard ratio (HR) 1.003; confidence interval (CI) 1.001-1.005; p = 0.009) and mean pulmonary artery pressure (HR 1.061; CI 1.024-1.100; p = 0.001) were found to significantly and independently predict outcomes for AL amyloidosis, whereas QRS duration (HR 1.021; CI 1.004-1.039; p = 0.013), hsTnT (HR 1.021; CI 1.006-1.036; p = 0.006) and N-terminal pro-brain natriuretic peptide (HR 1.0003; CI 1.0001-1.0004; p = 0.002) were the best predictors for ATTR amyloidosis. A simple risk score ("HeiRisk") including these parameters for AL and ATTR allowed a more precise risk stratification in our patient population compared to established risk models.

Conclusions: Risk stratification for cardiac amyloidosis with the newly developed "HeiRisk" score may be superior to other staging systems for patients with advanced heart failure due to amyloid cardiomyopathy.
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http://dx.doi.org/10.1007/s00392-019-01559-yDOI Listing
June 2020

Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis.

Nat Commun 2019 03 20;10(1):1103. Epub 2019 Mar 20.

Institute of Protein Biochemistry, Ulm University, 89081, Ulm, Germany.

Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis. They can be deposited in multiple organs but cardiac amyloid is the major risk factor of mortality. Here we report the structure of a λ1 AL amyloid fibril from an explanted human heart at a resolution of 3.3 Å which we determined using cryo-electron microscopy. The fibril core consists of a 91-residue segment presenting an all-beta fold with ten mutagenic changes compared to the germ line. The conformation differs substantially from natively folded light chains: a rotational switch around the intramolecular disulphide bond being the crucial structural rearrangement underlying fibril formation. Our structure provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity.
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http://dx.doi.org/10.1038/s41467-019-09032-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427026PMC
March 2019

AL amyloidosis with a localized B cell neoplasia.

Virchows Arch 2019 Mar 24;474(3):353-363. Epub 2019 Jan 24.

Department of Pathology, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3/14, D-24105, Kiel, Germany.

Immunoglobulin light chain-derived (AL) amyloidosis may occur as a systemic disease usually with dismal prognosis and a localized variant with favorable outcome. We report 29 patients with AL amyloidosis and associated lymphoplasmacytic infiltrate spatially related to amyloid deposits. In 17 cases, the amyloid deposits were classified as ALλ and 12 as ALκ Histopathology in all cases showed relatively sparse plasma cells and B cells without tumor or sheet formation by the lymphoplasmacytic infiltrate. The B cells predominantly showed an immunophenotype of the marginal zone. In situ, hybridization revealed 17 cases with λ- and 10 with κ light chain restricted plasma cells, which was concordant with the AL subtype in each case. Clonal immunoglobulin heavy variable gene (IGHV) or κ light chain rearrangement was found in 23/29 interpretable cases. A single case harbored a MYD88-mutation. Taken together, we detected 27 (93%) cases of AL amyloidosis with an associated light chain restricted and predominantly molecularly clonal plasma cell population. Clinical data were available in 18 patients. Five patients suffered from systemic lymphoma and two from systemic AL amyloidosis. The remaining cases were classified as localized with regard to both, the AL amyloidosis and the light chain restricted plasma cell population. To the best of our knowledge, we herein present the largest cohort of AL amyloidosis associated with a light chain restricted and predominantly molecularly clonal plasma cell population, which we designate as a distinct disease entity: "AL amyloidosis with a localized B cell neoplasia of undetermined significance".
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http://dx.doi.org/10.1007/s00428-019-02527-7DOI Listing
March 2019

Performance analysis of AL amyloidosis cardiac biomarker staging systems with special focus on renal failure and atrial arrhythmia.

Haematologica 2019 07 17;104(7):1451-1459. Epub 2019 Jan 17.

Department of Internal Medicine V, Division of Hematology/Oncology, Heidelberg University Hospital

Systemic light chain amyloidosis is a rare and life-threatening disorder, for which accurate risk stratification is crucial. Current cardiac staging systems (MAYO2004, MAYO3b, and MAYO2012) are mainly based on biomarkers, which have uncertain reliability in the context of atrial fibrillation, arrhythmia or pacemaker stimulation as well as renal insufficiency. We compared the performance of the established staging systems with particular regard to these comorbidities in 1,224 patients with systemic light chain amyloidosis diagnosed at our center from July 2002 until March 2017. We first characterized the subsets with an estimated glomerular filtration rate <50 mL/min/1.73 m (415 patients) and any kind of atrial arrhythmia (183 patients) as unique high-risk subgroups with similarly increased cardiac biomarkers (χ-test, all <0.001). This resulted in a shift towards higher risk stages and reduced median overall survival compared to those of patients with better kidney function or without atrial arrhythmia in univariate analyses (13 46 months and 17 53 months, respectively; both <0.001). Performance analysis revealed that predictions in the entire cohort were least precise with the MAYO2004 staging system and most precise with the MAYO3b system. This performance pattern was almost preserved for patients with an estimated glomerular filtration rate <50 mL/min/1.73 m, but less so for those with atrial arrhythmias. The MAYO3b staging system was most robust. Importantly, atrial arrhythmia retained its prognostic value in multivariable analysis including age, difference between involved and uninvolved free light chains, and any staging system, while estimated glomerular filtration rate <50 mL/min/1.73 m was not statistically significant in multivariable analysis with the MAYO3b staging system. In conclusion, our results favor the MAYO3b staging system due to its consistently best performance and retained applicability in the subgroups with atrial arrhythmia and estimated glomerular filtration rate <50 mL/min/1.73 m.
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http://dx.doi.org/10.3324/haematol.2018.205336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601086PMC
July 2019

Systemic immunoglobulin light chain amyloidosis.

Nat Rev Dis Primers 2018 10 25;4(1):38. Epub 2018 Oct 25.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Systemic immunoglobulin light chain amyloidosis is a protein misfolding disease caused by the conversion of immunoglobulin light chains from their soluble functional states into highly organized amyloid fibrillar aggregates that lead to organ dysfunction. The disease is progressive and, accordingly, early diagnosis is vital to prevent irreversible organ damage, of which cardiac damage and renal damage predominate. The development of novel sensitive biomarkers and imaging technologies for the detection and quantification of organ involvement and damage is facilitating earlier diagnosis and improved evaluation of the efficacy of new and existing therapies. Treatment is guided by risk assessment, which is based on levels of cardiac biomarkers; close monitoring of clonal and organ responses guides duration of therapy and changes in regimen. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, along with high-dose chemotherapy and autologous haematopoietic stem cell transplantation, have led to rapid and deep suppression of amyloid light chain production in the majority of patients. However, effective therapies for patients with advanced cardiac involvement are an unmet need. Passive immunotherapies targeting clonal plasma cells and directly accelerating removal of amyloid deposits promise to further improve the overall outlook of this increasingly treatable disease.
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http://dx.doi.org/10.1038/s41572-018-0034-3DOI Listing
October 2018

Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma.

Blood Adv 2018 10;2(20):2607-2618

Department of Medicine V, Hematology/Oncology/Rheumatology, University of Heidelberg, Heidelberg, Germany.

Analysis of intraclonal heterogeneity has yielded insights into the clonal evolution of hematologic malignancies. We compared the clonal and subclonal compositions of the underlying plasma cell dyscrasia in 544 systemic light chain amyloidosis (PC-AL) patients with 519 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or symptomatic MM; ie, PC-non-AL patients). Using interphase fluorescence in situ hybridization, subclones were stringently defined as clone size below two thirds of the largest clone and an absolute difference of ≥30%. Subclones were found less frequently in the PC-AL group, at 199 (36.6%) of 544 as compared with 267 (51.4%) of 519 in the PC-non-AL group ( < .001), and were not associated with the stage of plasma cell dyscrasia in either entity. In both groups, translocation t(11;14), other immunoglobulin heavy chain translocations, and hyperdiploidy were typically found as main clones, whereas gain of 1q21 and deletions of 8p21, 13q14, and 17p13 were frequently found as subclones. There were no shifts in the subclone/main clone ratio depending on the MGUS, SMM, or MM stage of plasma cell dyscrasia. In multivariate analysis, t(11;14) was associated with lower rates of subclone formation and hyperdiploidy with higher rates. PC-AL itself lost statistical significance, demonstrating that the lower subclone frequency in AL is a reflection of its exceptionally high t(11;14) frequency. In summary, the subclone patterns in PC-AL and PC-non-AL are closely related, implying that subclone formation depends on the main cytogenetic categories and is independent of disease entity and stage.
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http://dx.doi.org/10.1182/bloodadvances.2018023200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199662PMC
October 2018

Outcome of Patients With Newly Diagnosed Systemic Light-Chain Amyloidosis Associated With Deletion of 17p.

Clin Lymphoma Myeloma Leuk 2018 11 25;18(11):e493-e499. Epub 2018 Jul 25.

John C. Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA. Electronic address:

Introduction: Deletion 17p (del 17p) portends a poor prognosis in myeloma, but its significance in light-chain amyloidosis is unknown.

Patients And Methods: We identified patients with light-chain amyloidosis and del 17p at diagnosis, and analyzed presenting characteristics, treatments, and clinical outcomes. All had baseline biopsy results showing amyloid and serologic and marrow studies, including standard fluorescence in-situ hybridization determinations of del 17p using commercial probes. Consensus criteria for hematologic and organ involvement, progression, and response were used. Kaplan-Meier (log rank) analyses and Cox regression analysis of baseline variables were used to identify predictors of overall and progression-free survival (PFS). Six-month landmark analyses were performed to assess the impact of treatment-related variables.

Results: We identified 44 patients from 7 countries with median marrow and del 17p plasma cells of 22% (range, 3%-100%) and 30% (2%-93%). Ninety-five percent had cardiac involvement, including 44% stage III. Two-thirds of the patients initially received bortezomib-based therapy. Forty-nine percent of patients experienced complete response or very good partial response, with median time to best response of 4 months (range, 1-28 months). Median overall survival and PFS were 49 and 32 months. Cardiac stage and hematologic response were the key predictors of outcomes. Patients with > 50% and ≤ 50% del 17p in clonal plasma cells had median survivals of 28 and 52 months, respectively (P = .08). In landmark analyses, only hematologic response predicted both overall survival and PFS.

Conclusion: Cardiac stage, hematologic response, and del 17p percentage impact outcomes in these cases. Emphasis should be placed on optimizing supportive care and achieving a deep hematologic response.
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http://dx.doi.org/10.1016/j.clml.2018.07.292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441584PMC
November 2018

MR neurography biomarkers to characterize peripheral neuropathy in AL amyloidosis.

Neurology 2018 08 20;91(7):e625-e634. Epub 2018 Jul 20.

From the Department of Neuroradiology (J.K., S.H., T.H., M.P., M.B.), Amyloidosis Center Heidelberg (J.K., M.W., J.P., S.O.S., E.H., C.K., U.H.), Department of Neurology (M.W., J.P., E.H.), Division of Experimental Radiology, Department of Neuroradiology (S.H.), and Medical Department V (S.O.S., C.K., U.H.), Heidelberg University Hospital, Germany; Department of Neurology (J.M.H.), University of Michigan, Ann Arbor; and Department of Neuroradiology (M.P.), Würzburg University Hospital, Germany.

Objective: To detect, localize, and quantify peripheral nerve lesions in amyloid light chain (AL) amyloidosis by magnetic resonance neurography (MRN) in correlation with clinical and electrophysiologic findings.

Methods: We prospectively examined 20 patients with AL-polyneuropathy (PNP) and 25 age- and sex-matched healthy volunteers. After detailed neurologic and electrophysiologic testing, the patient group was subdivided into mild and moderate PNP. MRN in a 3.0 tesla scanner with anatomical coverage from the lumbosacral plexus and proximal thigh down to the tibiotalar joint was performed by using T2-weighted and dual-echo 2-dimensional sequences with spectral fat saturation and a 3-dimensional, T2-weighted inversion recovery sequence. Besides evaluation of nerve T2-weighted signal, detailed quantification of nerve injury by morphometric (nerve caliber) and microstructural MRN markers (proton spin density, T2 relaxation time) was conducted.

Results: Nerve T2-weighted signal increase correlated with disease severity: moderate (420.2 ± 60.1) vs mild AL-PNP (307.2 ± 17.9; = 0.0003) vs controls (207.0 ± 6.4; < 0.0001). Proton spin density was also higher in moderate (tibial: 525.5 ± 53.0; peroneal: 553.6 ± 64.5; sural: 492.0 ± 56.6) and mild AL-PNP (tibial: 431.6 ± 22.0; peroneal: 457.6 ± 21.7; sural: 404.8 ± 25.2) vs controls (tibial: 310.5 ± 14.1; peroneal: 313.6 ± 11.6; sural: 261.7 ± 11.0; < 0.0001 for all nerves). T2 relaxation time was elevated in moderate AL-PNP only (tibial: = 0.0106; peroneal: = 0.0070; sural: = 0.0190). Tibial nerve caliber was higher in moderate (58.0 ± 8.8 mm) vs mild AL-PNP (46.5 ± 2.5 mm; = 0.008) vs controls (39.1 ± 1.2 mm; < 0.0001).

Conclusions: MRN detects and quantifies peripheral nerve injury in AL-PNP in vivo with high sensitivity and in close correlation with the clinical stage. Quantitative parameters are feasible new imaging biomarkers for the detection of early AL-PNP and might help to monitor microstructural nerve tissue changes under treatment.
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http://dx.doi.org/10.1212/WNL.0000000000006002DOI Listing
August 2018

Obesity is a significant susceptibility factor for idiopathic AA amyloidosis.

Amyloid 2018 Mar 24;25(1):37-45. Epub 2018 Jan 24.

a Department of Medicine V, Amyloidosis Center and Division of Hematology, Oncology and Rheumatology , University of Heidelberg , Heidelberg , Germany.

Background: To investigate obesity as susceptibility factor in patients with idiopathic AA amyloidosis.

Methods: Clinical, biochemical and genetic data were obtained from 146 patients with AA amyloidosis. Control groups comprised 40 patients with long-standing inflammatory diseases without AA amyloidosis and 56 controls without any inflammatory disease.

Findings: Patients with AA amyloidosis had either familial Mediterranean fever (FMF) or long-standing rheumatic diseases as underlying inflammatory disease (n = 111, median age 46 years). However, in a significant proportion of patients with AA amyloidosis no primary disease was identified (idiopathic AA; n = 37, median age 60 years). Patients with idiopathic AA amyloidosis were more obese and older than patients with AA amyloidosis secondary to FMF or rheumatic diseases. Serum leptin levels correlated with the body mass index (BMI) in all types of AA amyloidosis. Elevated leptin levels of more than 30 µg/l were detected in 18% of FMF/rheumatic + AA amyloidosis and in 40% of patients with idiopathic AA amyloidosis (p = .018). Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for AA amyloidosis irrespective of the type of the disease.

Conclusions: Obesity, age and the SAA1 polymorphism are susceptibility factors for idiopathic AA amyloidosis. Recent advances in treatment of FMF and rheumatic disorders will decrease the incidence of AA amyloidosis due to these diseases. Idiopathic AA, however, might be an emerging problem in the ageing and increasingly obese population.
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http://dx.doi.org/10.1080/13506129.2018.1429391DOI Listing
March 2018

Melphalan 140 mg/m or 200 mg/m for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.

Haematologica 2018 03 7;103(3):514-521. Epub 2017 Dec 7.

University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Melphalan at a dose of 200 mg/m is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m and melphalan 140 mg/m are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m (n=245) and melphalan 200 mg/m (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m melphalan 140 mg/m: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m and melphalan 140 mg/m patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m or melphalan 140 mg/m for key transplant outcomes (NCT01362972).
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http://dx.doi.org/10.3324/haematol.2017.181339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830386PMC
March 2018

Improved outcomes after heart transplantation for cardiac amyloidosis in the modern era.

J Heart Lung Transplant 2018 05 15;37(5):611-618. Epub 2017 Nov 15.

Division of Cardiology, Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany. Electronic address:

Background: Cardiac amyloidosis, caused most commonly by deposition of light chain (AL) or transthyretin (ATTR) type fibrils, has an extremely poor prognosis. In this retrospective single-center study, we evaluated temporal trends in survival after heart transplantation for cardiac amyloidosis.

Methods: We analyzed 48 patients with cardiac amyloidosis (AL, n = 32; familial ATTR, n = 16) who underwent heart transplantation from May 2002 to March 2017. Patients were analysed in 2 periods, Era 1 (2002- 2007) and Era 2 (2008- 2017), separated by altered patient selection in both, AL and ATTR amyloidosis, and changed chemotherapy regimens for AL amyloidosis.

Results: The modern era was characterized by a lower number of extracardiac organ involvement for AL (94% isolated cardiac amyloidosis in Era 2 vs 56% in Era 1; p = 0.0221), and more frequent treatment for AL with the proteasome inhibitor bortezomib (94% in Era 2 vs 6% in Era 1; p < 0.0001). AL patients had significantly lower survival than patients with non-amyloid cardiomyopathy after heart transplantation in Era 1, and ATTR patients had numerically lower survival. However, survival in the modern era was comparable to non-amyloid transplants in both cohorts, possibly reflecting a shift in chemotherapy strategies and patient selection, respectively.

Conclusions: In the current era, use of enhanced chemotherapy regimens for isolated advanced AL cardiac amyloidosis was associated with outcomes comparable to non-amyloid cardiomyopathy. We conclude that heart transplantation in highly selected patients with isolated non-systemic advanced cardiac amyloidosis may be a feasible approach.
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http://dx.doi.org/10.1016/j.healun.2017.11.015DOI Listing
May 2018

First report of ibrutinib in IgM-related amyloidosis: few responses, poor tolerability, and short survival.

Blood 2018 01 27;131(3):368-371. Epub 2017 Nov 27.

Medical Department V, Amyloidosis Center, University Hospital Heidelberg, Heidelberg, Germany; and.

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http://dx.doi.org/10.1182/blood-2017-09-806463DOI Listing
January 2018

Diagnostic work up of an adult female patient with systemic AA amyloidosis revealing the cause of infantile mental retardation.

Amyloid 2018 Mar 23;25(1):68-69. Epub 2017 Nov 23.

a Department of Internal Medicine V, Amyloidosis Center , University of Heidelberg , Heidelberg , Germany.

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http://dx.doi.org/10.1080/13506129.2017.1405803DOI Listing
March 2018

Sural nerve injury in familial amyloid polyneuropathy: MR neurography vs clinicopathologic tools.

Neurology 2017 Aug 5;89(5):475-484. Epub 2017 Jul 5.

From the Department of Neuroradiology (J.K., S.H., M.P., M.B.), Amyloidosis Center Heidelberg (J.K., U.H., J.C.P., C.K., S.O.S., E.H., A.V.K., M.W.), Department of Neuropathology (F.S.), Medical Department V (U.H., C.K., S.O.S.), Department of Neurology (J.C.P., E.H., M.W.), Division of Experimental Radiology (S.H.), Department of Neuroradiology, and Medical Department III (A.V.K.), Heidelberg University Hospital; CCU Neuropathology (F.S.), German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany; Department of Neurology (J.M.H.), University of Michigan, Ann Arbor; Department of Pathology (C.R.), University of Kiel; and Department of Neuroradiology (M.P.), Würzburg University Hospital, Germany.

Objective: To detect and quantify lesions of the small-caliber sural nerve (SN) in symptomatic and asymptomatic transthyretin familial amyloid polyneuropathy (TTR-FAP) by high-resolution magnetic resonance neurography (MRN) in correlation with electrophysiologic and histopathologic findings.

Methods: Twenty-five patients with TTR-FAP, 10 asymptomatic carriers of the mutated transthyretin gene (mut), and 35 age- and sex-matched healthy controls were prospectively included in this cross-sectional case-control study. All participants underwent 3T MRN with high-structural resolution (fat-saturated, T2-weighted, and double-echo sequences). Total imaging time was ≈45 minutes per patient. Manual SN segmentation was performed from its origin at the sciatic nerve bifurcation to the lower leg with subsequent evaluation of quantitative microstructural and morphometric parameters. Additional time needed for postprocessing was ≈1.5 hours per participant. Detailed neurologic and electrophysiologic examinations were conducted in the TTR group.

Results: T2 signal and proton spin density (ρ) reliably differentiated between TTR-FAP (198.0 ± 13.3, 429.6 ± 15.25), mut carriers (137.0 ± 16.9, = 0.0009; 354.7 ± 21.64, = 0.0029), and healthy controls (90.0 ± 3.4, 258.2 ± 9.10; < 0.0001). Marked differences between mut carriers and controls were found for T2 signal ( = 0.0065) and ρ ( < 0.0001). T2 relaxation time was higher in patients with TTR-FAP only ( = 0.015 vs mut carriers, = 0.0432 vs controls). SN caliber was higher in patients with TTR-FAP vs controls and in mut carriers vs controls ( < 0.0001). Amyloid deposits were histopathologically detectable in 10 of 14 SN specimens.

Conclusions: SN injury in TTR-FAP is detectable and quantifiable in vivo by MRN even in asymptomatic mut carriers. Differences in SN T2 signal between controls and asymptomatic mut carriers are derived mainly from an increase of ρ, which overcomes typical limitations of established diagnostic methods as a highly sensitive imaging biomarker for early detection of peripheral nerve lesions.

Classification Of Evidence: This study provides Class III evidence that MRN accurately identifies asymptomatic mut carriers.
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http://dx.doi.org/10.1212/WNL.0000000000004178DOI Listing
August 2017

Centre characteristics and procedure-related factors have an impact on outcomes of allogeneic transplantation for patients with CLL: a retrospective analysis from the European Society for Blood and Marrow Transplantation (EBMT).

Br J Haematol 2017 08 7;178(4):521-533. Epub 2017 Jun 7.

Bone Marrow Transplantation Centre, University Hospital Eppendorf, Hamburg, Germany.

The best approach for allogeneic haematopoietic stem cell transplantations (alloHCT) in patients with chronic lymphocytic leukaemia (CLL) is unknown. We therefore analysed the impact of procedure- and centre-related factors on 5-year event-free survival (EFS) in a large retrospective study. Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five-year EFS of the whole cohort was 37% (95% confidence interval [CI], 34-42%). Larger numbers of CLL alloHCTs (hazard ratio [HR] 0·96, P = 0·002), certification of quality management (HR 0·7, P = 0·045) and a higher gross national income per capita (HR 0·4, P = 0·04) improved EFS. In vivo T-cell depletion (TCD) with alemtuzumab compared to no TCD (HR 1·5, P = 0·03), and a female donor compared to a male donor for a male patient (HR 1·4, P = 0·02) had a negative impact on EFS, but not non-myeloablative versus more intensive conditioning. After correcting for patient-, procedure- and centre-characteristics, significant variation in centre outcomes persisted. In conclusion, further research on the impact of centre and procedural characteristics is warranted. Non-myeloablative conditioning appears to be the preferable approach for patients with CLL.
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http://dx.doi.org/10.1111/bjh.14791DOI Listing
August 2017

AL amyloidosis patients with low amyloidogenic free light chain levels at first diagnosis have an excellent prognosis.

Blood 2017 08 26;130(5):632-642. Epub 2017 May 26.

Amyloidosis Center and.

The difference between involved minus uninvolved serum free light chains (dFLC) has been established as an invaluable hematologic parameter in systemic amyloid light chain (AL) amyloidosis. However, patients with an initial dFLC level <50 mg/L are currently deemed not evaluable for response to therapy. Therefore, we aimed to characterize this subgroup of patients and to define novel hematologic response parameters. We retrospectively analyzed 783 AL patients newly diagnosed at our center between 2002 and 2016. Patients with a dFLC level <50 mg/L showed smaller bone marrow plasmacytosis compared to patients with a dFLC level ≥50 mg/L (7% vs 10%, < .001), but no significant differences in all analyzed chromosomal aberrations. Cardiac involvement was less frequent (45% vs 80%, < .001) and less severe (Mayo 2004 stage III: 18% vs 51%, < .001), whereas kidney involvement was more prevalent (83% vs 53%, < .001) and proteinuria was higher (7.3 g/L vs 5.0 g/L, < .001). In multivariate analyses, a dFLC level <50 mg/L appeared to be an independent prognostic factor with respect to overall survival (hazard ratio [HR] = 0.50, = .003) and renal survival (HR = 0.56, = .020). Patients with a dFLC level <50 mg/L showed a higher proportion of complete hematologic response after first-line therapy compared to patients with a dFLC level ≥50 mg/L (39% vs 9%, < .001). Receiver-operating characteristics analysis identified a low-dFLC partial response (dFLC <10 mg/L for patients with a dFLC between 20 and 50 mg/L), which predicted overall and renal survival already at 3 months after the start of therapy. Importantly, a parallel Italian study validated this new hematologic remission parameter. The outcome of prospective clinical trials might be adversely influenced by exclusion of the favorable clinical subgroup with an initial dFLC <50 mg/L. We propose the appreciation of dFLC in hematologic response assessment for all patients with a baseline dFLC >20 mg/L.
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http://dx.doi.org/10.1182/blood-2017-02-767475DOI Listing
August 2017

A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis.

Blood 2017 08 26;130(5):597-605. Epub 2017 May 26.

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

This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902 A phase 3 study is ongoing (#NCT01659658).
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http://dx.doi.org/10.1182/blood-2017-03-771220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911836PMC
August 2017

Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up.

Haematologica 2017 08 18;102(8):1424-1431. Epub 2017 May 18.

Department of Internal Medicine, Division of Hematology/Oncology, University of Heidelberg, Germany.

Chemotherapy in light chain amyloidosis aims to normalize the involved free light chain in serum, which leads to an improvement, or at least stabilization of organ function in most responding patients. We performed a prospective single center phase 2 trial with 50 untreated patients not eligible for high-dose treatment. The treatment schedule comprised 6 cycles of oral lenalidomide, melphalan and dexamethasone every 4 weeks. After 6 months, complete remission was achieved in 9 patients (18%), very good partial remission in 16 (32%) and partial response in 9 (18%). Overall, organ response was observed in 24 patients (48%). Hematologic and cardiac toxicities were predominant adverse events. Mortality at 3 months was low at 4% (n=2) despite the inclusion of 36% of patients (n=18) with cardiac stage Mayo 3. After a median follow-up of 50 months, median overall and event-free survival were 67.5 months and 25.1 months, respectively. We conclude that the treatment of lenalidomide, melphalan and dexamethasone is very effective in achieving a hematologic remission, organ response and, consecutively, a long survival in transplant ineligible patients with light chain amyloidosis. However, as toxicity and tolerability are the major problems of a 3-drug regimen, a strict surveillance program is necessary and sufficient to avoid severe toxicities. .
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http://dx.doi.org/10.3324/haematol.2016.163246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541875PMC
August 2017

Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis.

Haematologica 2017 07 24;102(7):1281-1290. Epub 2017 Mar 24.

Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.

Immunoglobulin light chain (AL) amyloidosis is a rare plasma cell dyscrasia characterized by the deposition of abnormal amyloid fibrils in multiple organs, thus impairing their function. In the largest cohort studied up to now of 118 CD138-purified plasma cell samples from previously untreated immunoglobulin light chain amyloidosis patients, we assessed in parallel copy number alterations using high-density copy number arrays and interphase fluorescence hybridization (iFISH). We used fluorescence hybridization probes for the IgH translocations t(11;14), t(4;14), and t(14;16) or any other IgH rearrangement as well as numerical aberrations of the chromosome loci 1q21, 8p21, 5p15/5q35, 11q22.3 or 11q23, 13q14, 15q22, 17p13, and 19q13. Recurrent gains included chromosomes 1q (36%), 9 (24%), 11q (24%), as well as 19 (15%). Recurrent losses affected chromosome 13 (29% monosomy) and partial losses of 14q (19%), 16q (14%) and 13q (12%), respectively. In 88% of patients with translocation t(11;14), the hallmark chromosomal aberration in AL amyloidosis, a concomitant gain of 11q22.3/11q23 detected by iFISH was part of the unbalanced translocation der(14)t(11;14)(q13;q32) with the breakpoint in the gene region. Partial loss of chromosome regions 14q and 16q were significantly associated to gain 1q. Gain 1q21 detected by iFISH almost always resulted from a gain of the long arm of chromosome 1 and not from trisomy 1, whereas deletions on chromosome 1p were rarely found. Overall and event-free survival analysis found a potential adverse prognostic effect of concomitant gain 1q and deletion 14q as well as of deletion 1p. In conclusion, in the first whole genome report of clonal plasma cells in AL amyloidosis, novel aberrations and hitherto unknown potential adverse prognostic effects were uncovered.
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http://dx.doi.org/10.3324/haematol.2016.160721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566044PMC
July 2017

Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study.

Blood 2016 07 2;128(4):594-602. Epub 2016 Jun 2.

Amyloidosis Center, and Division of Hematology/Oncology/Rheumatology, Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany;

Cytogenetic aberrations detected by interphase fluorescence in situ hybridization (iFISH) of plasma cells are routinely evaluated as prognostic markers in multiple myeloma. This long-term follow-up study aimed to assess the prognosis of systemic light chain amyloidosis (AL) patients treated with high-dose melphalan (HDM) chemotherapy and autologous stem cell transplantation, depending on iFISH results. Therefore, we analyzed a consecutive cohort of 123 AL patients recruited from 2003 to 2014. HDM was safe, with only 1 of 123 patients dying as a result of treatment-related mortality, and effective, with a complete remission (CR) rate of 34%. Translocation t(11;14) as the most prevalent aberration (59%) led to an improved CR rate after high-dose therapy (41.2% vs 20.0%; P = .02), translating into a prolonged hematologic event-free survival (hemEFS; median, 46.1 vs 28.1 months; P = .05) and a trend for better overall survival (median, not reached vs 93.7 months; P = .07). In multivariate analysis, t(11;14) was confirmed as a favorable prognostic factor regarding hemEFS along with lower values for the difference between involved and uninvolved free light chains. Conversely, deletion 13q14, gain of 1q21, and hyperdiploidy had no significant prognostic impact. The high-risk cytogenetic aberrations t(4;14), t(14;16), and del(17p13) conferred an unfavorable prognosis, although statistical significance was reached only for univariate CR analysis in this small group of 9 patients. Thus, t(11;14) positivity in HDM-treated AL patients conferred superior CR rates and hemEFS. In view of the reduced response of t(11;14) to bortezomib, this highlights the impact of therapy on the prognostic role of cytogenetic aberrations.
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http://dx.doi.org/10.1182/blood-2015-10-676361DOI Listing
July 2016

Flow cytometry-based characterization of underlying clonal B and plasma cells in patients with light chain amyloidosis.

Cancer Med 2016 07 25;5(7):1464-72. Epub 2016 Apr 25.

Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.

Systemic amyloid light chain (AL) amyloidosis is a life-threatening protein deposition disorder; however, effective therapy can dramatically improve the prognosis of AL patients. Therefore, accurate diagnosis of the underlying hematologic disease is important. Multi-parameter flow cytometry (MFC) is a reliable method to analyze lymphatic neoplasias and to detect even a small lymphatic clone. We analyzed the presence of clonal plasma cell (PC) and B cells in the bone marrow of 63 patients with newly diagnosed AL amyloidosis by MFC. We compared the results with the levels of monoclonal protein, the histopathology and cytogenetic results. As reference of light chain restriction, we used the immunohistochemical results of κ or λ positive amyloid deposits in various tissues. MFC identified underlying clonal lymphatic cells in all but two patients (61 of 63, 97%). Sixty-one patients harbored malignant PCs, whereas B-cell lymphomas were identified in two patients. Furthermore, MFC indicated at least one putative immunotherapeutical target (CD20, CD38, CD52, or SLAMF7) on malignant PCs in all but one patient. These results demonstrate that MFC is a reliable tool for an accurate diagnosis of the underlying hematologic disease and the detection of potential immunotherapeutical targets in patients with AL amyloidosis.
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http://dx.doi.org/10.1002/cam4.725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944872PMC
July 2016