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

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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Serum Free Light Chain Responses after High-Dose Intravenous Melphalan and Autologous Stem Cell Transplantation for AL (Primary) Amyloidosis.

Blood ◽

10.1182/blood.v104.11.942.942 ◽

2004 ◽

Vol 104 (11) ◽

pp. 942-942

Author(s):

Vaishali Sanchorawala ◽

Daniel G. Wright ◽

Barbarajean Magnani ◽

Martha Skinner ◽

David C. Seldin

Keyword(s):

Stem Cell ◽

Plasma Cell ◽

Light Chain ◽

Free Light Chain ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Serum Free ◽

Hematologic Response ◽

Serum Free Light Chain

Abstract AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive deposition of amyloid fibrils derived from monoclonal Ig light chains, leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. Several approaches have been used to define hematologic responses of plasma cell dyscrasias underlying AL amyloidosis following HDM/SCT and other forms of treatment. The definition of a hematologic complete response (CR) that we have used requires that there be no evidence of a persistent monoclonal gammopathy by immunofixation electrophoresis (IFE) of serum and urine proteins, or of persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic response as a ≥ 50% reduction in free light chain (FLC) measurements. Hematologic responses by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a retrospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which hematologic CR, by our standard criteria, correlates with FLC response. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 67 patients with AL amyloidosis before and after treatment with HDM/SCT. After treatment with HDM/SCT, 27 patients (40%) achieved a CR by standard criteria. Of these 27 patients, 63% (n=17) demonstrated normalization of FLC levels and an improvement of ≥50% in FLC occurred in 100%. Of the 40 patients who did not achieve a CR, 25% (n=10) experienced normalization of FLC levels, and an improvement of ≥50% occurred in 78% (n=31), while only 5 patients (13%) experienced no significant change in FLC. The average improvement in FLC was 94% for patients who achieved a CR by standard criteria and 72% for those who did not (p=0.0001, t-test). Thus, HDM/SCT was found to induce improvements in FLC levels of ≥50% in the vast majority of AL amyloidosis patients treated with HDM/SCT (87%, or 58/67). These data indicate that a decrease in FLC of ≥50% is a substantially less stringent indicator of hematologic response than is CR, as defined by standard criteria. Nonetheless, these measures of hematologic response are complementary, since decreases in FLC can be detected earlier following treatment than changes in IFE and marrow studies required to determine CR.

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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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Deposition of Lambda Chain Constant Region within AL-Amyloid Lesion

Blood ◽

10.1182/blood.v124.21.3348.3348 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3348-3348

Author(s):

Hiroyuki Hata ◽

Masayoshi Tasaki ◽

Konen Obayashi ◽

Taro Yamashita ◽

Yukio Ando ◽

...

Keyword(s):

Mass Spectrometry ◽

Light Chain ◽

Mass Spectrometry Analysis ◽

Light Chains ◽

High Dose ◽

Al Amyloidosis ◽

Constant Region ◽

Rt Pcr ◽

Immunoglobulin Light Chain ◽

Lambda Light Chain

Abstract [Introduction] Diagnosis of AL amyloidosis is dependent on the proof of light chains in amyloid lesions. However, immunostaining does not always successfully prove the presence of light chains in lesions in AL amylidosis patients. Here we report that the constant region of immunoglobulin lambda light chain (IGLC2) is seen in amyloid lesions where no positive signals are found with regular immunostaining. [Materials and Methods] Amyloid samples were stained with anti-human lambda light chain antibody (DAKO PO-0130) and analyzed with mass-spectrometry combining laser micro-dissection. Bone marrow samples were obtained from patients with amyloidosis, who gave written informed consent, and were subjected to plasma cell purification using CD138-immunomagnetic beads. Expression of immunoglobulin light chain mRNA was examined with RT-PCR. Anti-human IGLL5 antibody, capable of detecting immunoglobulin light chain constant region 2 (IGLC2) in paraffin embedded samples, was utilized. [Results and Discussion] We performed immunostaining for immunoglobulin light chains with 18 samples and found that six and eight cases were positive for kappa and lambda light chains, respectively, whereas light chains were not detected in remaining four cases (immunostaining-negative amyloidosis; INA). However, interestingly, mass spectrometry analysis revealed the presence of IGLC2 in all of the INA cases. RT-PCR analysis revealed the presence of IGLC2 mRNA in plasma cells from such INA cases. Surprisingly, amyloid lesions in all of the INA cases were positively stained with anti-IGLL5 antibody, whereas no staining was found in other samples positively stained with DAKO PO-0130. These observations suggest that the deposition of IGLC2 may cause AL amyloidosis, which otherwise could not be diagnosed with regular immunostaining. Although high dose chemotherapy produced hematological remission, half of such cases died within one year, suggesting irreversible and life-threatening amyloid fibril depositions in critical organs in IGLC2-related cases. We further examined additional twelve cases with AL amyloidosis to determine the incidence of IGLC2-related amyloidosis by immunostaining. With regular immunostaining, kappa and lambda chain were found in three and five cases, respectively. Interestingly, the remaining four cases were negative with regular immunostaining but positive with anti-IGLL5 antibody. Taken these observations together, eight IGLC2-related amyloidosis cases and thirteen lambda type amyloidosis were identified. Thus, the incidence of IGLC2-related amyloidosis should be approximately 38% (8/21) among lambda type AL amyloidosis. We conclude that diagnosis of IGLC2-related AL amyloidosis was possible only with the use of anti-IGLL5 antibody, but not with regular immunostaining. Given the relatively high incidence and often poor prognosis of IGLC2-related amyloidosis, it is important that this clinical entity is recognized to potentially improve outcomes of treatments. Analysis of mechanisms regulating amyloid formation with IGLC2 peptides is currently underway. Disclosures No relevant conflicts of interest to declare.

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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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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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A pharmacist’s review of the treatment of systemic light chain amyloidosis

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155220963534 ◽

2020 ◽

pp. 107815522096353

Author(s):

David M. Hughes ◽

Andrew Staron ◽

Vaishali Sanchorawala

Keyword(s):

Multiple Myeloma ◽

Light Chain ◽

Case Reports ◽

Evidence Base ◽

Chemotherapeutic Agents ◽

Plasma Cell Dyscrasia ◽

High Dose ◽

Al Amyloidosis ◽

Tertiary Referral Center ◽

Treatment Considerations

Objective Systemic light-chain (AL) amyloidosis is an uncommon hematologic plasma cell dyscrasia that is becoming increasingly recognized. Therapeutic agents used in AL amyloidosis overlap with those used in multiple myeloma; however, differences in disease features change treatment efficacy and tolerance. Pharmacists must be cognizant of these distinctions. Herein, this review article provides an up-to-date guide to treatment considerations for systemic AL amyloidosis in both the front-line and relapsed settings. Data sources: A comprehensive literature search was performed using the PubMed/Medline database for articles published through (June 2020) regarding treatments for AL amyloidosis. Search criteria included therapies that are FDA approved for multiple myeloma, as well as investigational agents. This review of chemotherapeutic agents reflects the current clinical practice guidelines endorsed by NCCN along with commentary based on the experience of pharmacists from a tertiary-referral center treating many patients with AL amyloidosis. Data consists of randomized controlled trials, observational cohorts, case reports, and ongoing clinical trials. Data summary: Frontline options discussed here include high-dose melphalan with autologous stem cell transplantation and bortezomib-based regimens. Regarding the relapsed setting, supporting data are compiled and summarized for: bortezomib, ixazomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, elotuzumab, isatuximab, venetoclax, NEOD001, and melflufen. Conclusions The treatment platform for AL amyloidosis is expanding with novel agents traditionally used in multiple myeloma being adopted and modified for use in AL amyloidosis. The pharmacist’s familiarity with the clinical evidence base for these agents and how they fit into standard protocols for AL amyloidosis is critical as dosing and monitoring recommendations are unique from multiple myeloma.

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Hereditary systemic immunoglobulin light-chain amyloidosis

Blood ◽

10.1182/blood-2014-12-618108 ◽

2015 ◽

Vol 125 (21) ◽

pp. 3281-3286 ◽

Cited By ~ 6

Author(s):

Merrill D. Benson ◽

Juris J. Liepnieks ◽

Barbara Kluve-Beckerman

Keyword(s):

Light Chain ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Constant Region ◽

Immunoglobulin Light Chain ◽

Region Gene ◽

Dna Analyses ◽

Key Points ◽

Constant Region Gene ◽

Immunoglobulin Light Chain Amyloidosis

Key Points Protein and DNA analyses reveal that mutation in the immunoglobulin κ light-chain constant region gene may cause hereditary amyloidosis. Sequencing of immunoglobulin light-chain constant region genes is indicated for patients with AL amyloidosis and no evidence of a plasma cell dyscrasia.

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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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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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Acquired factor X deficiency in patients with amyloid light-chain amyloidosis: incidence, bleeding manifestations, and response to high-dose chemotherapy

Blood ◽

10.1182/blood.v97.6.1885 ◽

2001 ◽

Vol 97 (6) ◽

pp. 1885-1887 ◽

Cited By ~ 122

Author(s):

Elie B. Choufani ◽

Vaishali Sanchorawala ◽

Timothy Ernst ◽

Karen Quillen ◽

Martha Skinner ◽

...

Keyword(s):

Light Chain ◽

Medical Center ◽

Bleeding Complications ◽

Plasma Cell Dyscrasia ◽

High Dose ◽

Al Amyloidosis ◽

Related Factor ◽

Factor X ◽

Factor X Deficiency ◽

Amyloid Light Chain

Acquired deficiency of factor X occurs in patients with systemic amyloid light-chain (AL) amyloidosis, presumably due to adsorption of factor X to amyloid fibrils. Of 368 consecutive patients with systemic AL amyloidosis evaluated at Boston Medical Center, 32 patients (8.7%) had factor X levels below 50% of normal. Eighteen of these patients (56%) had bleeding complications, which were more frequent and severe in the 12 patients below 25% of normal; 2 episodes were fatal. Ten factor X–deficient patients received high-dose melphalan chemotherapy followed by autologous stem cell transplantation. Of 7 patients alive 1 year after treatment, 4 had a complete hematologic response, and all 4 experienced improvement in their factor X levels. One of 2 additional patients with partial hematologic responses had improvement in factor X. Thus, aggressive treatment of the underlying plasma cell dyscrasia in AL amyloidosis can lead to the amelioration of amyloid-related factor X deficiency.

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