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

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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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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Secretome Analyses of Primary Bone Marrow Fibroblasts Isolated From MGUS and Multiple Myeloma Show a Stepwise Occurrence of Alterations.

Blood ◽

10.1182/blood.v114.22.1801.1801 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1801-1801

Author(s):

Johannes Drach ◽

Astrid Slany ◽

Thomas Mohr ◽

Johannes Griss ◽

Christoph C Zielinski ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Growth Factor ◽

Plasma Cell ◽

Conflicts Of Interest ◽

Cell Clone ◽

Serum Levels ◽

Plasma Cell Dyscrasia ◽

Healthy Donors ◽

Bone Marrow Fibroblasts

Abstract Abstract 1801 Poster Board I-827 The microenvironment of tumor cells in the bone marrow was demonstrated to contribute to tumor promotion and survival. The role of bone marrow fibroblasts (BMFs) in supporting the malignant plasma cell clone in multiple myeloma (MM) has been established, but it remains unclear to which extent the BM microenvironment in general and BMFs in particular are involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. Therefore we performed proteomics studies on the secretome of BMFs isolated from healthy donors, patients suffering from MGUS and patients suffering from MM. Compared to normal background, BMFs derived from MGUS secreted elevated levels of proteins indicating mitogenic activity and moderate inflammation. These proteins included periostin, IL-6, CXCL5 and CSF-1. Insulin-like growth factor II, which is normally not expressed by normal BMFs, was secreted by BMF cells derived from MGUS as well as from MM. In addition to those and other proteins, BMF cells derived from MM were found to specifically secrete stem cell growth factor, MMP-28 and stanniocalcin-1. These data indicate a step-wise alteration of BMF secretion activity related to the stage of the underlying plasma cell dyscrasia. Therefore BMF might support the progression from MGUS to MM. In order to correlate the secretion performance of BMF with blood serum levels of candidate marker proteins, Luminex assays are employed. Based upon these results, it is our aim to identify serum biomarkers which allow to assess the functional state of BMF and thus the risk for the progression of MGUS to MM. Disclosures No relevant conflicts of interest to declare.

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Treatment in AL Amyloidosis: Moving towards Individualized and Clone-Directed Therapy

Hemato ◽

10.3390/hemato2040050 ◽

2021 ◽

Vol 2 (4) ◽

pp. 739-747

Author(s):

Ute Hegenbart ◽

Marc S. Raab ◽

Stefan O. Schönland

Keyword(s):

B Cell ◽

Plasma Cell ◽

Cell Clone ◽

Secretory Activity ◽

Underlying Disease ◽

Al Amyloidosis ◽

Cytogenetic Aberrations ◽

Plasma Cell Disorders ◽

Amyloid Light Chain ◽

Underlying Diseases

Systemic amyloid light chain (AL) amyloidosis is a rare protein deposition disease caused by a clonal B cell disorder of the bone marrow. The underlying diseases can be plasma cell disorders (monoclonal gammopathy of clinical significance, smoldering or symptomatic myeloma) or B cell non-Hodgkin’s lymphoma (e.g., Waldenstrom’s disease or marginal zone lymphoma) with secretory activity. It is crucial to characterize the underlying disease very precisely as the treatment of AL amyloidosis is directed against the (often small) B cell clone. Finally, the detection of cytogenetic aberrations of the plasma cell clone will likely play an important role for choosing an effective drug in the near future.

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99m Technetium-Hydroxy-Diphosphate Tracer (99mTcHDP) Bone Scintigraphy: An Easily Accessible, Rapid, Non-Invasive Diagnostic Tool for Cardiac Amyloidosis

Blood ◽

10.1182/blood.v128.22.3557.3557 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3557-3557

Author(s):

Simon DJ Gibbs ◽

Caroline Wong ◽

James Hare ◽

Hendrik Zimmet ◽

Jay Hocking ◽

...

Keyword(s):

Bone Scintigraphy ◽

Plasma Cell ◽

Cardiac Mri ◽

Cardiac Amyloidosis ◽

Conflicts Of Interest ◽

Troponin T ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Non Invasive ◽

Attr Patient

Abstract Aim: Cardiac amyloidosis is a protein deposition disease that can be difficult to diagnose and has a poor prognosis if diagnosis or treatment are delayed. The two major subtypes are AL and transthyretin (ATTR). Both have vastly different treatments so confirming the correct amyloid subtype is crucial. A tissue biopsy is usually required for the diagnosis of amyloidosis and to distinguish between the subtypes. No blood test, echocardiography or cardiac MRI can reliably distinguish between AL and ATTR. With a cardiac biopsy, distinguishing AL from ATTR can be challenging with immunohistochemistry, and time consuming with mass spectrometry. Recently, Gillmore et al demonstrated bone scintigraphy with 99mTc-DPD tracer can reliably diagnose ATTR, avoiding endomyocardial biopsies to confirm the subtype in most cases. [1] 99mTc-HDP is a tracer similar to 99mTc-DPD and is more readily available in Australian and the USA. We sought to examine the use of 99mTcHDP bone scintigraphy in Australia and determine the accuracy of this tracer to diagnose cardiac amyloidosis and distinguish between the AL and ATTR subtypes. Methods: All patients with confirmed ATTR or AL who had 99mTcHDP bone scintigraphy were analysed. Results were correlated with histology, NT ProBNP, Troponin-T, free light chains, cardiac MRI and echocardiography. Grading was conducted with Perugini scoring.[1] Results: 25 patients with amyloidosis diagnosed by cardiac MRI and/or biopsy, had 99mTcHDP bone scintigraphy. 18 were confirmed ATTR, 7 AL. Two ATTR patients had hereditary disease (Thy60Ala and Gly109Lys), the remainder were wildtype. 17 (94%) patients with ATTR and 2 (29%) AL had positive scans. The negative ATTR patient had localized bladder disease only with a normal echocardiogram and cardiac biomarkers. All ATTR patients with positive scans had Perugini scores of 2 or 3, including the 2 patients with hereditary mutations, while the two positive AL only had scores of 1. All 11 patients with amyloid features on cardiac MRI had positive scans. Mean NTproBNP values for ATTR and AL were 530pmol/L and 1396pmol/L respectively. The two AL amyloidosis patients with positive bone scans had higher NTproBNP values. No ATTR patient had a detectable plasma cell dyscrasia. Conclusion: Bone scintigraphy with 99mTcHDP tracer is an easily accessible, rapid and non-invasive method of diagnosing cardiac amyloidosis. In our small series, all patients with Perugini scores 2 or 3 had ATTR, while those with negative or Perugini score 1 scan either had AL or no cardiac amyloidosis. There was a suggestion that AL patients with higher NTproBNP scores were more likely to have positive scans. This suggests that the 99mTcHDP tracer can be used like 99mTc-DPD to aid in the diagnosis of cardiac amyloidosis, and, as suggested by Gillmore et al, can confirm the ATTR subtype in those with no detectable plasma cell dyscrasia and Perugini score 2 or 3 scans, thus hastening accurate diagnosis and avoiding cardiac biopsies. Reference: Gillmore JD, Maurer MS, Falk RH, Merlini M, Damy T, Dispenzieri A, et al. Non-biopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12 Disclosures No relevant conflicts of interest to declare.

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HGF Measurement in AL Amyloidosis.

Blood ◽

10.1182/blood.v114.22.1783.1783 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1783-1783

Author(s):

Julie Abraham ◽

Estelle Desport ◽

Benoit Marin ◽

Sebastien Bender ◽

Corinne Lacombe ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Roc Curve ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Renal Involvement ◽

Threshold Value ◽

Serum Levels ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis

Abstract Abstract 1783 Poster Board I-809 Purpose Hepatocyte Growth Factor (HGF) is a pro-angiogenic cytokine and a mitogenic, motogenic and morphogenic factor involved in tumor growth. Previous studies have shown that HGF is secreted by plasma cells in multiple myeloma and that HGF serum levels are higher in patients with multiple myeloma and correlate with disease activity. A previous study reported that serum HGF levels were significantly higher in patients with AL amyloidosis compared to patients with multiple myeloma (Iwasaki et al. Br J Haematol. 2002;116:796-802). A preliminary study of 18 AA and AL amyloidosis patients (Shikano et al, Intern Med. 2000;39:715-9) suggested that measurement of HGF might be useful for the diagnosis of amyloidosis. To determine whether HGF may be used as a relevant diagnosis marker and prognosis factor in AL amyloidosis, we have measured HGF serum levels in patients with AL amyloidosis and patients with plasma cell dyscrasia without amyloidosis. Patients and Methods Two groups of patients were included; patients with biopsy proven AL amyloidosis and patients with plasma cell dyscrasia (MGUS, multiple myeloma, POEMS) without amyloidosis as controls. Levels of HGF were measured by ELISA at diagnosis in the two groups, before any treatment (Quantikine® R&D Systems). Clinical features were recorded for AL patients. A Receiver Operating Characteristic curve (ROC) analysis was performed to assess the diagnostic accuracy of HGF for identification of amyloidosis cases among patients with monoclonal gammopathy. The area under the ROC curve (AUC) which can be interpreted as the probability that a randomly chosen amyloidosis patient has a test result greater than that of a randomly chosen non-amyloidosis patient, was calculated with its 95% confidence interval (95%CI). The ROC curve was also used to determine the best threshold for HGF. Using this threshold, sensitivity and specificity were calculated. Survival analyses were performed for patients suffering from AL amyloidosis. Baseline time was time from first HGF assessment to death or censoring date. Univariate analysis were done using Kaplan Meier and Cox proportional hazard models. Results Sixty-nine AL amyloidosis patients diagnosed between 2004 and 2008 and 76 controls (56 patients with MGUS, 17 with multiple myeloma, three with POEMS) were included. The median age was 61 (32-90) for AL patients and 60 (39-86) for controls. Median creatinine levels were respectively 86μmol/l (39-500) and 79μmol/l (44-317); 57 AL patients (82.6%) had renal involvement and 40 had (57.9%) cardiac disease. Monoclonal protein isotype was lambda in 69.6% of AL patients and kappa in 30.4%. HGF serum levels were significantly higher in patients with AL amyloidosis: 11.2ng/ml (0.5-200.4) compared with controls: 1.5ng/ml (0.8-8.2), p<0.0001 (healthy controls 0.9 ng/ml). HGF levels at diagnosis seemed to be discriminant with area under the ROC curve at 0.896 IC95% [0.834-0.94] p=0.0001. The threshold value of 2.4ng/ml conferred the best sensitivity : 82.6% IC95% [71.6-90.7] and specificity : 89.5% IC95% [80.3-95.3] for the diagnosis of AL amyloidosis. Patients were treated mainly by conventional chemotherapy (M-Dex), 65 % of AL patients were alive after a median follow up of 18 months. Univariate analysis showed a relative risk of mortality of 1.70 in AL patients with HGF levels upper than 11ng/ml, compared to those with HGF levels under 11 ng/l who showed a trend for better survival (p=0.22). Conclusion This study confirms that HGF levels are elevated in patients with AL amyloidosis, significantly higher than in patients with other plasma cell disorders. A threshold value of 2.4ng/ml confers a good sensitivity (80%) and specificity (90%) to suggest AL amyloidosis. HGF measurement may be used in patients with plasma cell dyscrasia to determine which patient should be considered for a biopsy. We found a trend towards reduced survival in patients with the highest levels of HGF. This, and the usefulness of HGF measurement in predicting clinical responses should be confirmed on larger studies. Disclosures No relevant conflicts of interest to declare.

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Conventional Therapy for Amyloid Light-Chain Amyloidosis

Acta Haematologica ◽

10.1159/000507072 ◽

2020 ◽

Vol 143 (4) ◽

pp. 365-372

Author(s):

Paolo Milani ◽

Giovanni Palladini

Keyword(s):

Stem Cell ◽

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Alkylating Agents ◽

Proteasome Inhibitors ◽

Response Rates ◽

Al Amyloidosis ◽

Cell Transplant ◽

Conventional Chemotherapy

The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.

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

Blood Advances ◽

10.1182/bloodadvances.2018023200 ◽

2018 ◽

Vol 2 (20) ◽

pp. 2607-2618 ◽

Cited By ~ 11

Author(s):

Tilmann Bochtler ◽

Maximilian Merz ◽

Thomas Hielscher ◽

Martin Granzow ◽

Korbinian Hoffmann ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Clonal Evolution ◽

Statistical Significance ◽

Hematologic Malignancies ◽

Absolute Difference ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Clone Size

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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Recent Advances in the Diagnosis, Risk Stratification, and Management of Systemic Light-Chain Amyloidosis

Acta Haematologica ◽

10.1159/000495455 ◽

2019 ◽

Vol 141 (2) ◽

pp. 93-106 ◽

Cited By ~ 28

Author(s):

Iuliana Vaxman ◽

Morie Gertz

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Proteasome Inhibitors ◽

Clinical Manifestations ◽

Al Amyloidosis ◽

Amyloid Deposits ◽

Protein Fibrils ◽

Risk Patients ◽

Intensive Search

The term amyloidosis refers to a group of disorders in which protein fibrils accumulate in certain organs, disrupt their tissue architecture, and impair the function of the effected organ. The clinical manifestations and prognosis vary widely depending on the specific type of the affected protein. Immunoglobulin light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, characterized by deposition of a misfolded monoclonal light-chain that is secreted from a plasma cell clone. Demonstrating amyloid deposits in a tissue biopsy stained with Congo red is mandatory for the diagnosis. Novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, venetoclax) and autologous stem cell transplantation, used for eliminating the underlying plasma cell clone, have improved the outcome for low- and intermediate-risk patients, but the prognosis for high-risk patients is still grave. Randomized studies evaluating antibodies that target the amyloid deposits (PRONTO, VITAL) were recently stopped due to futility and currently there is an intensive search for novel treatment approaches to AL amyloidosis. Early diagnosis is of paramount importance for effective treatment and prognosis, due to the progressive nature of this disease.

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Differential diagnosis of monoclonal gammopathy of undetermined significance

Hematology ◽

10.1182/asheducation.v2012.1.595.3798563 ◽

2012 ◽

Vol 2012 (1) ◽

pp. 595-603 ◽

Cited By ~ 57

Author(s):

Giampaolo Merlini ◽

Giovanni Palladini

Keyword(s):

Differential Diagnosis ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Cell Clone ◽

Organ Damage ◽

Organ Injury ◽

Al Amyloidosis ◽

Monoclonal Protein ◽

Undetermined Significance

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell disorder occurring in 4.2% of adults > 50 years of age, which can progress into symptomatic diseases either through proliferation of the plasma cell clone, giving rise to multiple myeloma and other lymphoplasmacellular neoplasms, or through organ damage caused by the monoclonal protein, as seen in light-chain amyloidosis and related conditions. Differential diagnosis of asymptomatic and symptomatic monoclonal gammopathies is the determinant for starting therapy. The criteria for determining end-organ damage should include markers of organ injury caused by the monoclonal protein. Patient assessment and optimal follow-up are now performed using risk stratification models that should also take into account the risk of developing AL amyloidosis. Patients with low-risk MGUS (approximately 40% of all MGUS patients) need limited assessment and very infrequent follow-up. The ongoing development of novel molecular biomarkers and advanced imaging techniques will improve the identification of high-risk patients who may benefit from early therapeutic intervention through innovative clinical trials.

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Second Autologous Peripheral Blood Stem Cell Transplantation with High Dose Melphalan (HDM/SCT) in Patients Relapsing After An Initial Course of HDM/SCT for the Treatment of AL Amyloidosis.

Blood ◽

10.1182/blood.v114.22.2318.2318 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2318-2318

Author(s):

Karen Quillen ◽

David C. Seldin ◽

Kathleen T. Finn ◽

Vaishali Sanchorawala

Keyword(s):

Stem Cell ◽

Conflicts Of Interest ◽

Plasma Cell Dyscrasia ◽

High Dose ◽

Time Interval ◽

Al Amyloidosis ◽

Clinical Relapse ◽

Cell Transplant ◽

Organ Function ◽

High Dose Melphalan

Abstract Abstract 2318 Poster Board II-295 High-dose melphalan and autologous stem cell transplant (HDM/SCT) can induce complete hematologic responses (CR), defined as disappearance of the underlying monoclonal gammopathy from serum and urine by immunofixation electrophoresis, and of the clonal plasma cell dyscrasia by bone marrow immunohistochemistry, and extend survival in patients with AL amyloidosis. HDM/SCT results in a CR in 40% of patients, and leads to clinical improvements in organ function in >70% of those who achieve a CR. However, hematologic and clinical relapses occur in ∼8% of patients who initially achieve a CR. Tandem cycles of HDM/SCT, which are typically performed within 12 months of each other, have been shown to achieve a higher ultimate CR rate of >60%. Among patients who do not achieve a CR following a single cycle of HDM/SCT, 30% nonetheless experience improvement in organ function. However, in this latter group, clinical improvement is not durable. We designed a study to explore the feasibility, and efficacy, of a second cycle of HDM/SCT in patients who relapse after initially responding to a first cycle of HDM/SCT. Results: Eleven patients, median age 55 (range 39-62), M:F 7:4, who had achieved hematologic and clinical responses after an initial cycle of HDM/SCT, were treated with a second cycle of HDM/SCT when a hematologic and/or clinical relapse occurred after a median time interval of 34 months (range 12-63). Five patients underwent a second course of G-CSF mobilization and a mean of 5.1 million (range 3.4-7.6 million) CD34 cells/kg was collected in a median of 2 days; the other patients had cells saved from the first mobilization. Six patients received 200 mg/m2 HDM; 5 patients received modified high-dose HDM at 140 mg/m2. Engraftment occurred at a median of 10 days for neutrophils, and 12 days for platelets (two days without platelet transfusion support); this engraftment timing is similar to that following the initial transplants (10 days for neutrophils, 13 days for platelets). There was no treatment-related mortality, but toxicity was moderate; almost all patients (except one) experienced grade III/IV non-hematologic toxicities. Of the 11 patients, 3 achieved hematologic CR at one year; these patients are alive and in continuous remission at 2-6 yr after the second transplant, including one patient who received a subsequent renal transplant. Three patients died of progressive disease at 1-2 years after the second transplant. Five patients are alive at 1-3 years post second transplant, in partial remission. Conclusion: 27% (3/11) of patients with AL amyloidosis who experience a hematologic or clinical relapse after responding to initial HDM/SCT can achieve a hematologic CR with a second course of HDM/SCT. Disclosures: No relevant conflicts of interest to declare.

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