Systemic AL amyloidosis with an undetectable plasma cell dyscrasia: A zebra without stripes

Abstract 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 (P < .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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Localized AL Amyloidosis of the Breast: A Case Series.

Blood ◽

10.1182/blood.v114.22.4906.4906 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4906-4906

Author(s):

Marjory Charlot ◽

David C. Seldin ◽

Carl O'Hara ◽

Martha Skinner ◽

Vaishali Sanchorawala

Keyword(s):

Plasma Cell ◽

Congo Red ◽

Conflicts Of Interest ◽

Amorphous Material ◽

Case Series ◽

Screening Mammography ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Palpable Mass ◽

Amyloid Deposits

Abstract Abstract 4906 AL amyloidosis is characterized by widespread, progressive deposition of fibrillar amyloid protein derived from monoclonal immunoglobulin light chains, leading to organ failure and death. This disease is typically systemic, however, it can occur as a localized form. In localized amyloidosis, the deposits occur near the site of synthesis of the precursor protein and in some cases, plasma cells have been demonstrated histologically adjacent to the deposits. For unknown reasons, the tracheobronchial tree is the most common site for localized AL amyloidosis. Localized AL amyloidosis of the breast is a rare entity that has been described in the literature in isolated case reports. It can present as a palpable mass or as calcifications on routine screening mammography. We report here a case series of seven women (median age 63 years, range 46 to75) seen and evaluated at Boston University Medical Center from 1990-2008. We evaluated 1502 new patients with AL amyloidosis in this time period, making the incidence of localized AL amyloidosis of the breast to be 0.5% at a single referral center. All seven patients had abnormal screening mammography with calcifications, and biopsies that revealed Congo red positive amyloid deposits. Histologically, the amyloid deposits appeared as amorphous material in the stroma around the ducts and lobules in most patients; one patient had amyloid deposits in the ducts only, but not in the stroma. None of the patients had clinical or laboratory evidence of other organ involvement, all had negative Congo red staining of an abdominal fat pad aspirate, and all had a negative work up for a plasma cell dyscrasia or circulating paraprotein. The patients were treated with local excision of the regions of calcification or lumpectomy. Three out of seven patients underwent routine follow up within 6-12 months from the time of diagnosis with no evidence of disease recurrence or progression to systemic AL amyloidosis. One out of seven patients had bilateral and recurrent amyloidosis of the breasts and was found to have an associated stage I invasive ductal adenocarcinoma that was treated with lumpectomy and radiation. In summary, breast amyloidosis is rare, is not associated with a systemic plasma cell dyscrasia or amyloidosis in other organs, and can be treated surgically. Disclosures No relevant conflicts of interest to declare.

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Frequency of Amyloid Subtyping Among Patients with Immunoglobulin Light-Chain Amyloidosis Referred for High-Dose Chemotherapy and Autologous Stem Cell Transplant

Blood ◽

10.1182/blood.v128.22.5601.5601 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5601-5601

Author(s):

Andrew J. Cowan ◽

David G. Coffey ◽

Teresa S. Hyun ◽

Pamela S. Becker ◽

Damian J. Green ◽

...

Keyword(s):

Mass Spectrometry ◽

Plasma Cell ◽

Light Chain ◽

Congo Red ◽

Plasma Cell Dyscrasia ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Immunoglobulin Light Chain ◽

Organ Systems

Abstract Background: The amyloidoses comprise a heterogeneous group of diseases characterized by misfolding of amyloidogenic proteins and subsequent deposition as amyloid fibrils. To date, over 30 proteins are known to be amyloidogenic (Sipe Amyloid 2014). Immunoglobulin light chain (AL) amyloidosis, a plasma cell dyscrasia, is the most common subtype. The standard diagnostic algorithm in AL amyloidosis is to obtain a biopsy of a clinically involve organ, and once Congo red positivity is confirmed, perform subtyping analyses with immunohistochemistry or mass spectrometry. Accurate subtyping of amyloidosis is essential to appropriate treatment, as misdiagnosis occurs in up to 10% of patients and may lead to inappropriate administration of chemotherapy (Comenzo Blood 2006; Lachmann NEJM 2002). We sought to determine the patterns of amyloid subtyping among patients with a diagnosis of AL amyloidosis referred to a tertiary referral center for HDM/SCT. Methods: Sequential patients with confirmed amyloidosis, age ≥ 18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were eligible. Presence of a Congo red-positive biopsy for each patient referred for transplant was confirmed and the pathology reports and medical records were reviewed to determine if subtyping was performed, and which modality was used. Results: Fifty-one patients with AL amyloidosis were referred for transplant; of these, 45 proceeded with HDM/SCT. The organ systems most commonly involved were renal in 34/51, and gastrointestinal in 5/51. Of the biopsies, subtyping was performed in 35 (68.6%), and no subtyping was performed in 16 patients (31.3%). Immunofluorescence was the most common modality used for subtyping in 33 biopsies (94.2%) and laser capture/mass spectrometry (LC/MS) was used in 2 patients (5.7%). All patients had evidence of a clonal plasma cell dyscrasia by bone marrow biopsy and peripheral blood testing. Of the patients without subtyping, 8 (50%) were diagnosed before 2008. Discussion: Misdiagnosis of amyloidosis due to a lack of appropriate subtyping is a well-described and ongoing problem for patients with amyloidosis. These data suggest that definitive subtyping is still not routinely performed in the evaluation of amyloidosis. At our center, efforts to standardize the evaluation of Congo-red positive biopsies using definitive typing are underway. Disclosures Gopal: Seattle Genetics: Research Funding.

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Safety and Tolerability of Cael-101 in Combination with Anti-Plasma Cell Dyscrasia Therapy in Patients with AL Amyloidosis: 1-Year Results from an Open-Label Phase 2 Trial

Blood ◽

10.1182/blood-2021-153636 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 468-468

Author(s):

Jason Valent ◽

Jeffrey A. Zonder ◽

Michaela Liedtke ◽

John Silowsky ◽

Michael R. Kurman ◽

...

Keyword(s):

Board Of Directors ◽

Plasma Cell ◽

Amyloid Fibrils ◽

Renal Involvement ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Phase 2 ◽

Open Label ◽

Advisory Committees ◽

Phase 2 Trial

Abstract Background: AL amyloidosis, a rare, severe, progressive, systemic disorder caused by plasma cell dyscrasia (PCD), results in insoluble immunoglobulin light chain amyloid fibrils depositing in organs and causing significant dysfunction, morbidity, and mortality. Most patients receive anti-PCD therapy as standard of care (SOC) to suppress plasma cell proliferation and arrest the generation and deposition of new amyloid fibrils. At present, no approved therapies exist that target fibrils already deposited. CAEL-101, a monoclonal antibody, binds to amyloid light chain fibrils and promotes removal from tissues. In this Phase 2 trial, patients were treated with doses up to 1000 mg/m 2, combined with SOC, demonstrating this dose was well tolerated and appropriate for Phase 3. Aim: Evaluate long-term safety and tolerability of CAEL-101, administered with SOC in AL amyloidosis. Methods: Adult patients with confirmed AL amyloidosis diagnosis (Mayo Stages I, II, IIIa), 6-month minimum life expectancy, and measurable hematologic disease were eligible for this ongoing, open-label, phase 2 study (NCT04304144). Patients with other forms of amyloidosis, multiple myeloma, supine systolic blood pressure <90 mm Hg, or symptomatic orthostatic hypotension were excluded. All patients received CAEL-101 1000mg/m 2 every other week with SOC anti-PCD therapy until investigator decided anti-PCD was no longer needed (Figure). Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory tests, electrocardiograms, vital signs, and physical examinations. Pharmacokinetic endpoints included maximum serum concentration (C max) and minimum serum concentration of CAEL-101 prior to next dose (C trough). Exploratory endpoints included biomarkers for cardiac function (cardiac troponin T [cTnT] and N-terminal pro-brain natriuretic peptide [NT-proBNP]), and renal function (estimated glomerular filtration rate and proteinuria). Results: The 25 patients averaged 65.2 years (range 47 to 80), with the majority male (72.0%). Mayo Stages I (8.0%), II (76.0%), and IIIa (16.0%) reflected the wide range of disease severity in enrolled patients ; 19 (76.0%) presented with cardiac involvement, 8 (32.0%) with renal involvement, and 20 (80.0%) had received prior anti-PCD therapy. Twenty-four (96.0%) patients experienced TEAEs, but only 6 (24.0%) experienced a possibly treatment related TEAE (Table). Eight (32.0%) patients experienced at least 1 Grade ≥3 TEAE and 7 (28.0%) experienced at least 1 serious adverse event. There were 3 (12.0%) discontinuations; 1 death due to septic pneumonia (investigator determined not related to CAEL-101), one heart transplant, and one patient who withdrew consent. Most common TEAEs included nausea (9 [36.0%]], constipation (8 [32.0%]), and diarrhea, fatigue, or rash (7 [28.0%] each). Addition of daratumumab (n = 12) to the anti-PCD combination treatment of cyclophosphamide-bortezomib-dexamethasone (CyBorD) did not alter the pharmacokinetic or tolerability profile of CAEL-101. Of the 19 current cardiac evaluable patients (baseline NT-proBNP ≥332 ng/L and ≥1 post-first-dose NT-proBNP value), 15 (78.9%) have responded (≥ 30% NT-proBNP decrease from baseline) or are stable on CAEL-101 therapy. Renal evaluable patients, as determined by Investigator at a single site, showed a similar proteinuria response. Discussion: This ongoing trial is evaluating the long-term safety and tolerability of CAEL-101 administered with anti-PCD SOC as a treatment to reduce amyloid burden in patients with cardiac AL amyloidosis. CAEL-101 was well tolerated when administered with anti-PCD therapy. Most TEAEs observed were mild to moderate in severity and did not require intervention. There were no meaningful differences in tolerability or exposure to CAEL-101 when daratumumab was added to the anti-PCD regimen. Improvements in cardiac and renal response biomarkers were observed in most patients presenting with cardiac or renal involvement, respectively, at study entry. Conclusion: After approximately 1-year, CAEL-101, as part of an AL amyloidosis treatment strategy, demonstrates to be well tolerated. This updated report confirms previous findings for the use of CAEL-101 in combination with anti-PCD. A Phase 3 clinical program is ongoing to further elucidate the efficacy and safety of CAEL-101. Figure 1 Figure 1. Disclosures Valent: Takeda Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau; Caelum Biosciences: Other: Clinical Trial Funding; Celgene Corporation: Speakers Bureau. Zonder: Caelum Biosciences: Consultancy; Regeneron: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy; BMS: Consultancy, Research Funding. Liedtke: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Silowsky: Caelum Biosciences: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Daniel: Caelum Biosciences: Current Employment. Jobes: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Raviwong: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Sobolov: Caelum Biosciences: Current Employment.

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Renal Pathologic Spectrum in an Autopsy Series of Patients With Plasma Cell Dyscrasia

Archives of Pathology & Laboratory Medicine ◽

10.5858/2004-128-875-rpsiaa ◽

2004 ◽

Vol 128 (8) ◽

pp. 875-879 ◽

Cited By ~ 7

Author(s):

Guillermo A. Herrera ◽

Lija Joseph ◽

Xin Gu ◽

Aubrey Hough ◽

Bart Barlogie

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Renal Infarction ◽

Light Chain Deposition Disease ◽

Renal Lesions ◽

Cast Nephropathy ◽

Plasma Cell Dyscrasias ◽

Light Chain Deposition

Abstract Context.—Renal dysfunction in plasma cell dyscrasias is common. It is the second most common cause of death in patients with myeloma. Objective.—We evaluated 77 sequential autopsies performed on patients dying from complications of plasma cell dyscrasias during an 11-year period at the University of Arkansas for Medical Sciences. These consisted of 15% of all the autopsies performed during this time. Design.—The kidneys were evaluated by light microscopy using hematoxylin-eosin–stained sections as well as Congo red and thioflavin T stains when amyloidosis was in the differential diagnosis. Immunofluorescence was performed on selected cases. Results.—The most common lesion identified was cast nephropathy (30%). Other findings included acute tubulopathy, AL-amyloidosis, light chain deposition disease, tubulointerstitial nephritis associated with monotypic light chain deposits, thrombotic microangiopathy, renal infarction, fungal infection, and plasma cell tumor nodules. Autolysis, an expected finding in autopsy evaluations, was significant in 25 cases. Conclusions.—Renal lesions are heterogeneous in these patients. In some cases, combined pathologic lesions were noted. Myeloma cast nephropathy predominated among all the renal lesions noted.

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Plasma Cell Gene-Expression Profiles in Patients with Systemic AL Amyloidosis: Responses to Melphalan and Stem Cell Transplant Are Associated with Differential Expression of Genes Involved in Translation, Protein Degradation and Detoxification.

Blood ◽

10.1182/blood.v106.11.3405.3405 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3405-3405

Author(s):

Raymond L. Comenzo ◽

Ping Zhou ◽

Limin Wang ◽

Stephen D. Nimer ◽

Adam B. Olshen

Keyword(s):

Gene Expression ◽

Protein Degradation ◽

Plasma Cell ◽

Plasma Cells ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Gene Families ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Cell Transplant

Abstract Systemic AL amyloidosis is a plasma cell dyscrasia and protein conformation disorder in which Ig light chains (Ig VL) produced by clonal plasma cells form interstitial amyloid in key viscera causing organ dysfunction and death. Patients with AL usually have < 20% marrow plasma cells with low to nil proliferative indices. Paradoxically the plasma cells appear immune to the toxic amyloid-forming Ig VL possibly due to the robust cytoplasmic protein quality-control processes in plasma cells. A standard approach is to treat with high-dose melphalan and stem cell transplant (SCT) without induction therapy. Post-SCT long-term survival depends on significant reductions of the plasma cell disease and Ig VL levels as measured by the serum free light chain (FLC) assay. At 3 months post-SCT responses of the plasma cell dyscrasia are defined both by standard criteria and by normalization of abnormal FLC ratios. By standard criteria, post-SCT one-third fail to achieve a > 50% reduction in plasma cell disease (NR), one-third achieve a > 50% reduction (PR), and one-third achieve clearance of marrow plasma cells and a complete or near complete response (CR). By FLC criteria, post-SCT one-third achieve normalization (N) of the FLC ratio and two-thirds do not (A). Many factors contribute to this distribution of responses. In order to identify factors specific to AL plasma cells, gene expression profiles (GEP; Affymetrix U133 PLUS 2.0) were obtained after double amplification of RNA from FACS-sorted CD138+/DAPI- plasma cells from untreated patients with AL pre-SCT. Data were vetted based on plasma cell lineage gene expression; samples contaminated with monocytes were not used. Supervised analyses were performed based on responses at 3 months post-SCT, comparing CR (n=4) to PR (n=7) and CR to NR (n=5), and FLC N (n=5; one with CR) to A (n=7; two with CR). Differentially expressed genes between paired sets were identified using the t-test. Genes with p < 0.01 were examined using EASE, a program that identifies over-represented gene families. In the CR-PR and CR-NR comparisons, genes involved in translation, RNA ligation and protein degradation, particularly aminoacyl tRNA synthetases, were significantly over-represented with Bonferroni-adjusted EASE scores (like p-values) < 0.05. In the CR set, tryptophanyl tRNA synthetase, a protein that can also be anti-angiogenic, and IDE, an insulin-degrading enzyme that also degrades Aβ amyloid peptides, were among the most over-expressed. In the FLC N-A comparison, protein transport and detoxification gene families were also significantly over-represented with Bonferroni-adjusted EASE scores < 0.001. In the N set, CCT subunits (chaperones), UBE2B (a ubiquitination enzyme and RAD6 homolog) and glyoxalase I (detoxification) were among the most over-expressed. Our initial hypothesis is that the CR and FLC N responses to melphalan have similar but distinctive GEP related to protein folding, ER stress and protein degradation. The responses of AL plasma cells to Ig VL in the ER may influence the patterns observed, possibly modulating melphalan uptake or activity. Further studies of these differences and functional hypothesis testing are currently underway.

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Treatment of AL Amyloidosis with Tandem Cycles of High Dose Melphalan and Autologous Stem Cell Transplantation: Final Analysis of a Prospective Trial.

Blood ◽

10.1182/blood.v108.11.612.612 ◽

2006 ◽

Vol 108 (11) ◽

pp. 612-612

Author(s):

Vaishali Sanchorawala ◽

Daniel G. Wright ◽

Karen Quillen ◽

Laura M. Dember ◽

John L. Berk ◽

...

Keyword(s):

Stem Cell ◽

Clinical Improvement ◽

Plasma Cell ◽

Initial Treatment ◽

Performance Status ◽

Prospective Trial ◽

Plasma Cell Dyscrasia ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant

Abstract AL amyloidosis is caused by a clonal plasma cell dyscrasia and is characterized by widespread, progressive amyloid deposition leading to multisystem organ failure and death. In this disease, amyloid protein deposits are derived from monoclonal immunoglobulin light chains. Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. Furthermore, we have observed in over 300 patients treated with HDM/SCT that achievement of a hematologic complete response (CR), i.e. disappearance of monoclonal gammopathy and clonal plasma cell dyscrasia, is a critical determinant of clinical improvement and prolonged survival. Because of the importance of hematologic CR in treatment outcome, we conducted a prospective trial to determine whether a second cycle of HDM/SCT would induce a hematologic CR in patients in whom the plasma cell dyscrasia persisted following initial treatment with HDM/SCT. Additional objectives of the trial were to determine the feasibility and tolerability of tandem cycles of HDM/SCT in AL amyloidosis. Eligibility for entry into the trial required evidence of plasma cell dyscrasia, age < 65 years, ≤ 300 mg of prior oral melphalan, and minimal measures of performance status (SWOG ≤ 2) and cardiopulmonary function (LVEF > 45%, DLCO > 50%). Peripheral blood stem cells were collected by leukapheresis following G-CSF mobilization, with minimum yields of 7.5 x 106 CD34+ cells/kg required for participation in the trial. From 11/2000 to 6/2005, 62 patients, median age 55.5 (range 32–65), M: F ratio 1.8:1.0, were enrolled. Of the 62 patients enrolled, 9 (15%) were removed from the protocol either because of an inadequate stem cell collection (7) or because of complications during stem cell mobilization and collection that precluded treatment with HDM/SCT (2). Of the 53 patients who received the first cycle of 200 mg/m2 HDM, 4 patients died within 100 days of treatment (8%), and 27 (55%) were found to have achieved a hematologic CR 6 months after HDM/SCT. Of the 22 patients who did not achieve a CR after initial treatment, 17 patients received a second HDM/SCT with 140 mg/m2 of IV melphalan. Mortality within 100 days after this second treatment was 6% (1/17), while 27 % (4/15) of surviving patients achieved a hematologic CR by 6 months following the second cycle of HDM/SCT. Therefore, for the patients treated with one or two cycles of HDM/SCT on this study, the ultimate hematologic CR rate was 63% (31/49). With a median follow up of 38 months (range, 14–69 months), the median survival for all patients enrolled has not yet been reached. Moreover, improvements in amyloid related organ dysfunction, particularly in nephrotic syndrome, liver involvement, neuropathy and/or performance status, were evident in all patients who achieved a hematologic CR. In conclusion, tandem cycles of HDM/SCT are tolerable for selected patients with AL amyloidosis and can increase the proportion of patients who ultimately achieve a hematologic CR.

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Hyperdiploidy Is Rare in Patients with AL Amyloidosis – Identification of Major Cytogenetic Groups in Early Monoclonal Plasma Cell Disorders.

Blood ◽

10.1182/blood.v114.22.2823.2823 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2823-2823 ◽

Cited By ~ 1

Author(s):

Tilmann Bochtler ◽

Ute Hegenbart ◽

Christiane Heiss ◽

Axel Benner ◽

Stephanie Pschowski-Zuck ◽

...

Keyword(s):

Plasma Cell ◽

Multiple Testing ◽

Conflicts Of Interest ◽

Cell Clone ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Inverse Association ◽

Chromosome 11 ◽

Tree Model ◽

Cytogenetic Aberrations

Abstract Abstract 2823 Poster Board II-799 AL amyloidosis (AL) is characterized by the deposition of amyloid fibrils in diverse tissues due to an underlying monoclonal plasma cell dyscrasia. In a previous study (Bochtler et al, Blood 2008) we have demonstrated that in AL cytogenetic aberrations were detectable in about 90% of patients (pts). Translocation t(11;14) proved to be the most frequent aberration in AL found in 45% of the pts. In this study we evaluated whether the concept of hyperdiploidy and non-hyperdiploidy as major pathogenetic pathways in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is also applicable to AL. Our study was based on the largest patient group tested for cytogenetics in AL thus far including 184 pts with AL - among them 21 pts with concomitant MM I. They were assessed for their ploidy status by interphase fluorescence in situ hybridization (FISH). 179 MGUS and MM I pts not requiring therapy served as controls. We used a well established score (Wuilleme et al, Leukemia 2005), which requires extra copies for at least two out of the three probes 5p15/5q35, 9q34 and 15q22 as criterion for hyperdiploidy. The hyperdiploidy frequency was very low in AL with 14% as compared to 32% in MGUS / MM I (p<0.001). Among AL pts those with a concomitant MM I displayed a higher hyperdiploidy frequency than those without (43% versus 10%, p<0.001) suggesting that chromosomal gains reflect progression of the monoclonal plasma cell clone. Addressing hyperdiploidy probes in detail, we could show that both in the 184 pts. with AL and 179 pts. with MGUS / MM I gains of 11q23, 17p13 and 19q13.3 closely clustered with the three hyperdiploidy defining probes 5p15/5q35, 9q34 and 15q22 (p'0.01 for all probes after adjusting for multiple testing). However, gain of 11q23 was also frequently detected in association with t(11;14). The group with gain of 11q23 subdivides into a t(11;14) positive and a hyperdiploidy positive subgroup in both the AL (p<0.001) and the MGUS / MM I (p<0.001) entities. As revealed by additional probes for 11p15 and 11cen, gain of 11q23 in hyperdiploid pts reflected a gain of the whole chromosome 11 in all tested pts (10 AL and 31 MGUS / MM I). On the contrary, gain of 11q23 in t(11;14) positive pts was merely due to the translocation involving chromosome 11 (with 25 out of 26 AL and 5 out of 7 MGUS / MM I pts displaying a normal diploid status for 11p15 and 11cen). Therefore, gain of 11q23 is a poor indicator of hyperdiploidy in AL, where t(11;14) frequencies are particularly high and hyperdiploidy frequencies are particularly low. Addressing the cytogenetic clustering of hyperdiploidy with other cytogenetic aberrations we observed a strong inverse association of hyperdiploidy with t(11;14) in both AL and MGUS / MM I (p<0.001 in both entities). Accordingly, both aberrations were allocated to branches separating from each other already at the root in the oncogenetic tree model (see figure 1). Del13q14/t(4;14) and IgH translocations with an unknown partner also separated as distinct branches early from the root. These similar clustering patterns of both AL and MGUS / MM I with 4 major cytogenetic groups suggests common pathogenetic mechanisms in both entities despite their differing hyperdiploidy and t(11;14) frequencies. Disclosures: No relevant conflicts of interest to declare.

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Multiple endocrine neoplasms in a patient with AL amyloidosis-associated plasma cell dyscrasia

Endocrine Pathology ◽

10.1007/bf02739944 ◽

1997 ◽

Vol 8 (2) ◽

pp. 153-160

Author(s):

Kunihiko Seki ◽

Shingo Wakatsuki ◽

Kazuo Hizawa ◽

Tadashi hasegawa ◽

Yuichi Fujinaka ◽

...

Keyword(s):

Plasma Cell ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis

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Amyloidosis and Plasma Cell Dyscrasias: A Single Institution Experience

Blood ◽

10.1182/blood-2019-131577 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5463-5463

Author(s):

Poornima Ramadas ◽

Ajay Tambe ◽

Mijung Lee

Keyword(s):

Mass Spectrometry ◽

Plasma Cell ◽

Light Chain ◽

Cardiac Involvement ◽

False Negative ◽

Protein Electrophoresis ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Negative Mass ◽

High Clinical Suspicion

Background: Amyloidosis is the extracellular tissue deposition of small molecular subunits of proteins as fibrils. AL Amyloidosis is a complication of underlying plasma cell dyscrasia with an associated monoclonal paraprotein. It can occur in association with multiple myeloma (MM), Waldenstrom macroglobulinemia (WM) or non-Hodgkin lymphoma. While isolated organ involvement can be seen, many patients (pts) have multiorgan involvement. Our aim was to explore the trend of amyloidosis associated with plasma cell dyscrasia, treatment and outcome at our institution. Methods: After IRB approval, we reviewed medical records of adult pts ≥ 18 years with a histological diagnosis of amyloid and had evidence of monoclonal gammopathy, between January 1st, 2010 and June 30th, 2019. We reviewed age at diagnosis, gender, work up for paraproteinemia, site of biopsy, technique used for identification of amyloid, imaging studies, treatment and outcome. Results: We found a total of 33 pts with biopsy proven amyloid and evidence of a monoclonal paraprotein. 23 (69.6%) were males and 10 (30.3%) were females. Age ranged from 39 to 89 years with a median age of 62; 3 (9%) being <50 years. 7 (21.2%) were diagnosed with multiple myeloma and one pt each was diagnosed with diffuse large B cell lymphoma and WM. Monoclonal paraprotein was IgG Kappa in 10 (30.3%), IgG lambda in 5 (15%), IgA lambda in 3 (9%), IgA kappa in one, IgM lambda in 3 (9%), IgM Kappa in one, kappa light chain in 5 (15.1%), lambda light chain in 3 (9%), one had both IgG lambda and IgM kappa and no paraprotein was documented in one pt. Serum protein electrophoresis with immunofixation was positive in 22 (66.6%), Urine protein electrophoresis and immunofixation was positive in 16 (48.4%). Most common initial site of amyloid identification by biopsy was kidney in 12 (36.3%). Diagnosis was from abdominal fat pad in 8 (24.2%), lung in 4 (12.1%), bone marrow, heart and skin in 2 each (6%) and liver, colon and bone in 1 each (3%). Positive immunohistochemistry (IHC) stain demonstrating light chain restriction was seen in 23 (69.6%) and out of this only 11 (33%) underwent further evaluation with mass spectrometry. One patient with positive IHC had negative mass spectrometry despite high clinical suspicion for AL amyloidosis. IHC was not performed in 8 (24.2%) and identification was only based on Congo red staining. IHC was negative in 2 (6%) despite evidence of a monoclonal paraprotein. Involvement of kidney was identified in 14 (42.4%) with isolated kidney involvement in 2 (6%). Cardiac involvement was identified in 17 (51.5%) either by biopsy, imaging findings and/or pro-BNP and troponin levels and isolated cardiac disease was noted in 3 (9%). 6 (18.1%) had lung involvement, which was the only disease site in 4 (12.1%). Neuropathy was noted in 10 (30.3%). One had only a single bony site involved. 21 (63.6%) were treated with disease related therapy for amyloidosis, one patient underwent radiation to site of isolated bone disease and the remaining patients were either observed or died before therapy was initiated. 7 (21%) underwent Autologous stem cell transplant for amyloidosis. At the time of data cut off, 21 (63.6%) were alive and 12 (36.3%) were deceased. Amyloidosis was the documented cause of death in 10 pts and of this 9 pts had cardiac involvement. Conclusion: AL Amyloidosis is an uncommon disorder and patients should undergo further diagnostic evaluation if suspicious symptoms with an underlying monoclonal gammopathy. In our study, we noted a male predominance and IgG Kappa was the most common monoclonal paraprotein. As immunohistochemistry has a greater chance of false positive and false negative results, mass spectrometry is the preferred method for identification of amyloid. However, this technique is not widely available which restricts it's use in clinical practice. In our study, we identified one patient with positive IHC who had negative mass spectrometry despite high clinical suspicion for AL amyloidosis. We also identified two patients with negative IHC despite evidence of a monoclonal paraprotein and this may be either a false negative IHC or the amyloid being unrelated to the monoclonal paraprotein. 9/10 pts who died of amyloidosis had cardiac involvement. Disclosures No relevant conflicts of interest to declare.

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