scholarly journals Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 549-557 ◽  
Author(s):  
Ping Zhou ◽  
Julie Teruya-Feldstein ◽  
Ping Lu ◽  
Martin Fleisher ◽  
Adam Olshen ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Calcium Binding ◽  
Plasma Cells ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Embryonic Fibroblasts ◽  
Knock Out ◽  
High Dose Melphalan

In high doses with stem-cell transplantation, melphalan is an effective but toxic therapy for patients with systemic light-chain (AL-) amyloidosis, a protein deposition and monoclonal plasma cell disease. Melphalan can eliminate the indolent clonal plasma cells that cause the disease, an achievement called a complete response. Such a response is usually associated with extended survival, while no response (a less than 50% reduction) is not. Gene-expression studies and a stringently supervised analysis identified calreticulin as having significantly higher expression in the pretreatment plasma cells of patients with systemic AL-amyloidosis who then had a complete response to high-dose melphalan. Calreticulin is a pleiotropic calcium-binding protein found in the endoplasmic reticulum and the nucleus whose overexpression is associated with increased sensitivity to apoptotic stimuli. Real-time PCR and immunohistochemical staining also showed that expression of calreticulin was higher in the plasma cells of those with a complete response. Furthermore, wild-type murine embryonic fibroblasts were significantly more sensitive to melphalan than calreticulin knock-out murine embryonic fibroblasts. These data have important implications for understanding the activity of melphalan in plasma-cell diseases and support further investigation of calreticulin and its modulation in patients with systemic AL-amyloidosis receiving high-dose melphalan.

The frequency of chromosomal abnormalities in AL amyloidosis and their impact on treatment response.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19539-e19539
Author(s):  
Hassan Yameen ◽  
Shayna Sarosiek ◽  
Vaishali Sanchorawala
Keyword(s):  
Plasma Cells ◽  
Response Rate ◽  
Chromosomal Abnormalities ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Response Data ◽  
Hematologic Response ◽  
Number Of Patients ◽  
High Dose Melphalan

e19539 Background: Chromosomal abnormalities (CA) found in AL amyloidosis (AL) are similar to those found in multiple myeloma (MM.) However, t(11;14) has been reported more frequently in AL, anywhere from 30% - 50% in studies. It has been reported that the presence of t(11;14) confers a lower hematologic response rate with bortezomib-based therapy (BBT) and a better hematologic response rate with high dose melphalan and autologous stem cell transplantation (HDM/SCT). Methods: We performed a retrospective review of 307 newly diagnosed patients seen at our center between January 2013 and December 2017, for whom interphase fluorescent in-situ hybridization (iFISH) data, performed on bone marrow aspirate using standard MM FISH probes on enriched plasma cells after magnetic separation, were available. Patients who already had iFISH performed prior to their visit with us were also included. We collected data on the incidence of CA, first line treatment, and hematologic response to this treatment. Results: Of the 307 patients, CA were not detected in 37%. 21% had t(11;14), 25% had 13q deletion, 21% had IgH rearrangements with an undetermined partner chromosome, and 11% had 1q21 gain. In those for whom initial treatment and hematologic response data were available, in patients with t(11;14), hematologic complete response (CR) was achieved by 18% following HDM/SCT and 27% following BBT. For those with 1q21 gain, CR was achieved by 33% following HDM/SCT and 19% following BBT. In contrast, hematologic CR was achieved by 47% following HDM/SCT and 40% following BBT for those who had no detectable CA with iFISH. Conclusions: Our study shows a lower incidence of t(11;14) in AL compared to other studies. This may be partly explained by the high number of patients with IgH rearrangements with undetermined partner chromosomes, some of whom may indeed harbor t(11;14). Our study also did not show a better hematologic response rate with HDM/SCT in t(11;14) patients compared with BBT. Hematologic response rates were much better both with HDM/SCT and BBT for those with no detected CA compared to patients who had t(11;14) or 1q21 gain.

Early Serum Free Light Chain Responses Following High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4352-4352
Author(s):  
Saulius Girnius ◽  
Frank Tsai ◽  
David C. Seldin ◽  
Karen Quillen ◽  
Lisa Yanarella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Light Chain ◽  
Predictive Value ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
High Dose Melphalan

Abstract Abstract 4352 AL amyloidosis is a clonal plasma cell dyscrasia which produces insoluble amyloid fibrils from Ig light chains, leading to multiorgan failure. High dose melphalan and autologous stem cell transplantation (HDM/SCT) can induce remission and extend survival, but response is assessed at 6 and 12 months. Serum free light chain (FLC) assays can improve detection of AL amyloidosis, have prognostic significance, and are routinely used to assess response to treatment. Serum half life of FLCs is only 2-6 hours, even with diminished glomerular filtration rates. In a small prospective series, we previously reported that FLC levels 1-3 weeks after HDM/SCT correlate with hematologic response at 1 year. This study was performed to confirm these results on a larger scale. A prospective analysis of patients with AL amyloidosis treated with HDM/SCT was performed to determine the extent to which early FLC responses predict hematologic complete response (CR). Exclusion criteria included initial normal FLC concentrations and ratios and chronic renal insufficiency (Cr>1.2 mg/dL) with a normal FLC ratio. Hematologic responses, as defined by standard traditional criteria, were determined at 6 and 12 months. Traditional criteria define hematologic CR as by normalization of bone marrow exam and absence of monoclonal gammopathy in urine and serum by immunofixation electrophoreses. Serum FLC concentrations were measured by a sensitive nephelometric analysis within 10 days and within 3 weeks of HDM/SCT. Complete response for serum FLC was defined as normalization of FLC concentration and ratio or normalization of the ratio in renal failure (Cr>1.2 mg/dL). Serum FLC levels or k/l FLC ratios were abnormal and informative in 124 patients (87%) prior to HDM/SCT, and these patients were included in subsequent analyses. One week after transplant, sensitivity of FLC to predict hematologic CR was 0.64, specificity was 0.67, positive predictive value (PPV) was 0.49, negative predictive value (NPV) was 0.79, positive likelihood ratio (LR) was 1.92, and negative LR was 0.54. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.36, specificity was 0.86, PPV was 0.54, NPV was 0.75, positive LR was 2.59, and negative LR was 0.74. Two to three weeks after transplant, sensitivity of FLC CR to predict hematologic CR was 0.72, specificity was 0.74, PPV was 0.57, NPV was 0.85, positive LR was 2.78, and negative LR was 0.38. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.34, specificity was 0.86, PPV was 0.52, NPV was 0.74, positive LR was 2.40, and negative LR was 0.77. Serum FLC concentrations within 3 weeks of HDM/SCT have poor predictive values and should not be used to predict hematologic CR. However, failure to reduce FLC concentrations by 90% has a somewhat higher negative predictive value and could be used to guide additional post-transplant management. Disclosures: No relevant conflicts of interest to declare.

Defining Complete Response in Multiple Myeloma: Role of the Serum Free Light Chain Assay and Multiparameter Flow Cytometry.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1479-1479 ◽  
Author(s):  
Roger G. Owen ◽  
J. Anthony Child ◽  
Andy C. Rawstron ◽  
Sue Bell ◽  
Kim Cocks ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Light Chain ◽  
Plasma Cells ◽  
Complete Response ◽  
Free Light Chain ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Reference Laboratory ◽  
Serum Free ◽  
Serum Free Light Chain

Abstract It is becoming increasingly clear that the use of immunofixation (IF) to define complete response (CR) in MM has its limitations. Paraprotein concentration is not a direct measure of tumour bulk and maximal responses may take many months to achieve which inevitably underestimate CR rates in therapeutic schedules that contain the sequential use of different agents. The purpose of this study was to prospectively assess the applicability and value of the serum free light chain (SFLC) assay and multiparameter flow cytometry (MFC) to assess CR in the intensive pathway of the MRC Myeloma IX Trial. In this trial patients are initially randomised to induction with CVAD or CTD and patients with stable disease or better proceed to high dose melphalan (HDM) with stem cell support. There is a second randomisation to maintenance thalidomide or no further therapy. SFLC as well as standard serum and urine paraprotein assessments were performed in a central reference laboratory at the following time points: presentation, end of induction, day 100 post HDM and 3 monthly until relapse. Similarly MFC in which neoplastic plasma cells are identified and differentiated from normal plasma cells on the basis of CD19 and CD56 expression was evaluated (again in a central laboratory) at presentation, end of induction and day 100 following HDM and annually until relapse. An initial analysis of 207/1114 randomised patients was performed and the results are detailed below - End of induction Day 100 post HDM IF negative 16.3% 49.4% SFLC normal 46.1% 78.6% MFC negative 10.2% 50.7% The SFLC assay was informative in 95% of patients and provided for a more rapid assessment of response than conventional methods. A normal SFLC assay at the end of induction appeared to predict for attainment of an IF-neg CR at day 100 (70% IF-neg CR if SFLC normal vs 30% when SFLC abnormal at the end of induction). It should however be noted that 58% of patients who failed to achieve an IF-neg CR at day 100 had a normal SFLC assay. MFC provides for a direct assessment of residual neoplastic plasma cells. The assay was informative in 96.7% of patients and has a reproducible sensitivity of 0.01%. The majority of patients (89.8%) had detectable disease at the end of induction with a median of 0.7% neoplastic plasma cells (range 0.01–14%). Further cytoreduction was provided by the HDM such that 49.3% had flow detectable disease at day 100 with a median of 0.26% neoplastic plasma cells (range 0.02–8%). 30% of patients with IF-neg CR had detectable disease while 21% of patients with a persistent paraprotein had no detectable disease in their marrow. The majority of the latter patients had IgG paraproteins and it is postulated that many of these pts will ultimately achieve an IF-neg CR. We would conclude that given the kinetics of paraprotein clearance in MM it may be more appropriate to define CR on the basis of a normal SFLC assay and the absence of minimal residual disease by MFC. In this way it should be possible to more accurately define the CR rate achieved by individual components of multi-agent sequential regimens.

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Differences and Similarities in Treatment Paradigms and Goals Between AL Amyloidosis and Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 680-691
Author(s):  
Monique C. Minnema ◽  
Rimke Oostvogels ◽  
Reinier Raymakers ◽  
Margot Jak
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Residual Disease ◽  
Intensive Treatment ◽  
High Dose ◽  
Al Amyloidosis ◽  
Treatment Schedule ◽  
Bone Marrow Plasma ◽  
High Dose Melphalan

Although there are similarities in the treatment paradigms between AL amyloidosis and multiple myeloma, there are also fundamental differences. A similarity is of course the use of anti-plasma cell drugs in both diseases; however, the most serious mistake a hemato-oncologist can make is to use the same treatment schedule in dosing and frequency in AL amyloidosis patients as in multiple myeloma patients. AL amyloidosis patients with >10% bone marrow plasma cell infiltration in particular are at risk of receiving a more intensive treatment than they can tolerate. This difference in dosing and frequency is true for many anti-clonal drugs, but it is most apparent in the use of high-dose melphalan and autologous stem cell transplantation. While in multiple myeloma in the age group of ≤70 years, more than 80% of patients are fit enough to receive this intensive treatment, this is the case in less than 20% of AL amyloidosis patients. A similarity is the alignment in the goal of treatment. Although in AL amyloidosis has long been recognized that the goal should be complete hematological remission, this has become more apparent in multiple myeloma in recent years. A common goal in the coming years will be to evaluate the role of minimal residual disease to improve survival in both diseases.

scholarly journals In Vitro and inVivo Activity of Melflufen in Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3100-3100 ◽  
Author(s):  
Ken Flanagan ◽  
Muntasir M Majumder ◽  
Romika Kumari ◽  
Juho Miettinen ◽  
Ana Slipicevic ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Lines ◽  
Plasma Cell ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Advisory Committees

Background: Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by plasma cell secretion of misfolded light chains that assemble as amyloid fibrils and deposit on vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell directed therapeutics, aimed at preferentially eliminating the clonal population of amyloidogenic cells in bone marrow are expected to reduce production of toxic light chain and alleviate deposition of amyloid thereby restoring healthy organ function. Melphalan flufenamide ethyl ester, melflufen, is a peptidase potentiated alkylating agent with potent toxicity in myeloma cells. Melflufen is highly lipophilic, permitting rapid cellular uptake, and is subsequently enzymatically cleaved by aminopeptidases within cells resulting in augmented intracellular concentrations of toxic molecules, providing a more targeted and localized treatment. Previous data demonstrating multiple myeloma plasma cell sensitivity for melflufen suggests that the drug might be useful to directly eliminate amyloidogenic plasma cells, thereby reducing the amyloid load in patients. Furthermore, the increased intracellular concentrations of melflufen in myeloma cells indicates a potential reduction in systemic toxicity in patients, an important factor in the fragile amyloidosis patient population. To assess potential efficacy in amyloidosis patients and to explore the mechanism of action, we examined effects of melflufen on amyloidogenic plasma cells invitro and invivo. Methods: Cellular toxicity and apoptosis were measured in response to either melflufen or melphalan in multiple malignant human plasma cell lines, including the amyloidosis patient derived light chain secreting ALMC-1 and ALMC-2 cells, as well as primary bone marrow cells from AL amyloidosis patients, using annexin V and live/dead cell staining by multicolor flow cytometry, and measurement of cleaved caspases. Lambda light chain was measured in supernatant by ELISA, and intracellular levels were detected by flow cytometry. To assess efficacy of melflufen in vivo, the light chain secreting human myeloma cell line, JJN3, was transduced with luciferase and adoptively transferred into NSG mice. Cell death in response to melflufen or melphalan was measured by in vivo bioluminescence, and serum light chain was monitored. Results: Melflufen demonstrated increased potency against multiple myeloma cell lines compared to melphalan, inducing malignant plasma cell death at lower doses on established light chain secreting plasma cell lines. While ALMC-1 cells were sensitive to both melphalan and melflufen, the IC50 for melphalan at 960 nM was approximately 3-fold higher than melflufen (334 nM). However, ALMC-2 cells were relatively insensitive to melphalan (12600 nM), but maintained a 100-fold increase in sensitivity to melflufen (121 nM). Furthermore, while 40% of primary CD138+ plasma cells from patients with diagnosed AL amyloidosis responded to melflufen treatment in vitro, only 20% responded to melphalan with consistently superior IC50 values for melflufen (Figure 1). Light chain secreting cell lines and AL amyloidosis patient samples were further analyzed by single cell sequencing. We further examined differential effects on apoptosis and the unfolded protein response in vitro in response to either melflufen or melphalan. This is of particular interest in amyloidosis, where malignant antibody producing plasma cells possess an increased requirement for mechanisms to cope with the amplified load of unfolded protein and associated ER stress. As AL amyloidosis is ultimately a disease mediated by secretion of toxic immunoglobulin, we assessed the effects of melflufen on the production of light chain invitro, measuring a decrease in production of light chain in response to melflufen treatment. Finally, we took advantage of a recently described adoptive transfer mouse model of amyloidosis to assess the efficacy of melflufen and melphalan in eliminating amyloidogenic clones and reducing the levels of toxic serum light chain in vivo. Conclusions: These findings provide evidence that melflufen mediated toxicity, previously described in myeloma cells, extends to amyloidogenic plasma cells and further affects the ability of these cells to produce and secrete toxic light chain. This data supports the rationale for the evaluation of melflufen in patients with AL amyloidosis. Figure 1 Disclosures Flanagan: Oncopeptides AB: Employment. Slipicevic:Oncopeptides AB: Employment. Holstein:Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy. Lehmann:Oncopeptides AB: Employment. Nupponen:Oncopeptides AB: Employment. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding.

Early Serum Free Light Chain Responses Following High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis Predict Treatment Outcomes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1160-1160
Author(s):  
Vaishali Sanchorawala ◽  
Daniel G. Wright ◽  
Karen Quillen ◽  
Catherine Fisher ◽  
Martha Skinner ◽  
...  
Keyword(s):  
Stem Cell ◽  
Treatment Outcomes ◽  
Light Chain ◽  
Free Light Chain ◽  
High Dose ◽  
Al Amyloidosis ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Treatment Responses ◽  
High Dose Melphalan

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 following HDM/SCT and other forms of treatment. The standard 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 a persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic responses according to reductions in free light chain (FLC) measurements. Treatment responses as defined by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a prospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which early FLC responses within weeks of treatment predict hematologic CR, as defined by our standard criteria. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 31 patients with AL amyloidosis, between 2003–2005, 1–3 weeks after treatment with HDM/SCT. Hematologic responses, as defined by standard criteria, as well as FLC responses were subsequently determined at 3, 6 and 12 months. Serum FLC levels or κ/λ FLC ratios were abnormal and informative in 28 patients (90%) prior to HDM/SCT, and these patients were included in subsequent analyses. Twenty patients (71%) achieved normalization of abnormal serum FLC levels or ratios within 1–3 weeks of undergoing HDM/SCT. Of these 20 patients, 13 patients (65%) subsequently achieved a hematologic CR as defined by standard criteria, while 7 (35%) did not, within 3 months following HDM/SCT. In contrast, none of the 8 patients with no demonstrable FLC response within 1–3 weeks of HDM/SCT, were found to have achieved a hematologic CR subsequently. In conclusion, meaningful quantitative FLC responses (or lack of response) can be detected within weeks following HDM/SCT treatment that predict hematologic responses, as defined subsequently by standard criteria based on IFE and marrow studies (p=0.0018 by chi square analysis). Moreover, a lack of an early FLC response predicts for hematologic non-CR. We anticipate that prospective studies of FLC responses in HDM/SCT and other clinical trials for AL amyloidosis will eventually lead to more rapid assessment of treatment responses that will guide therapeutic decisions.

B Type Natriuretic Peptide (BNP) Less Than 200 Pg/Ml Represents Good Candidate For High Dose Melphalan and Predicts Longer Survival In Systemic Light Chain Amyloidosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5523-5523
Author(s):  
Toshiaki Hayashi ◽  
Hiroshi Ikeda ◽  
Yuka Aoki ◽  
Yumiko Maruyama ◽  
Tadao Ishida ◽  
...  
Keyword(s):  
Diastolic Function ◽  
Natriuretic Peptide ◽  
Light Chain ◽  
Contractile Function ◽  
Performance Status ◽  
Conditioning Regimen ◽  
High Dose ◽  
Al Amyloidosis ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Background High dose melphalan with autologous stem cell transplantation (ASCT) is a standard treatment for eligible patients with systemic light chain (AL) amyloidosis. Treatment-related mortality (TRM) of ASCT for AL amyloidosis was previously reported being as high as 40%; however, risk-adapted melphalan dosing reduced TRM to about 10% or less in experienced institutes. Several ways to determine the dose of melphalan have been proposed. They were focusing on organ failures especially cardiac dysfunction shown by ejection fraction (EF). EF represents contractile function of the heart; however, in AL amyloidosis, EF is known to be maintained until late stage whereas diastolic function is damaged earlier. We here present the outcomes of AL patients who received ASCT following risk-adapted melphalan with our criteria including B type natriuretic peptide (BNP) which is a practical marker for diastolic function of the heart and less affected by the renal function than NT-proBNP. Patients and Methods A total of 12 patients with primary systemic AL amyloidosis treated with HD-Mel with ASCT at Sapporo Medical University Hospital between 2004 and 2012 were evaluated. Patients with age older than 65 years, poor performance status or severe organ dysfunction were determined not to eligible for ASCT. The dose of melphalan for conditioning regimen was modified due to patients' condition. A dose of 200 mg/m2 was administered to patients in performance status (ECOG) 0 or 1, number of organ involvement 2 or less, serum creatinine <1.5 mg/dl, EF >50%, and BNP <200 pg/ml; otherwise 140 mg/m2. Hematological response (HR) and organ response (OR) were evaluated according to the Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis. The Kaplan-Meier method was used to estimate event-free survival (EFS) and overall survival (OS); both of them were measured from the day of ASCT. Results Twelve patients were included in this study, 4 were women. The median age at transplantation was 54 years (range, 32 - 65 years). Involvement of 1 organ was present in 1 patient (8.3%), 2 organs were involved in 8, and 3 or more organs in the remaining 3. Ten patients had a lambda monoclonal protein, and the median percentage of plasma cells in the bone marrow was 2.5% (range, 0.2% - 9.6%). No patients received treatment before HDM/ASCT, except 2 patients treated high-dose dexamethasone or 1 course of VAD regimen before referring to our hospital. Six patients received 200 mg/m2 of melphalan and remaining six received reduced dose based on the criteria in Patient and Methods. Notably, it was possible to screen patients with only the value of BNP; i.e., all the patients who received 140 mg/m2 of melphalan by the criteria had a high level (more than 200 pg/ml) of BNP. The median time from diagnosis of AL to ASCT was 95 days (range, 47 to 195 days). The median number of CD34-positive cells infused was 3.55 x106/kg, and all patients were engrafted. The hematologic CR was achieved in 5 patients and PR in 2. The organ response was observed in 2 patients who achieved hematologic CR. The median EFS of all patients was 21.1 months (range, 3.4 to 70.8 months), and median OS was 21.1 months (range, 3.4 to 112.5 months). EFS and OS were significantly longer for patients who received 200 mg/m2 of melphalan that are same with patients who had BNP less than 200 pg/ml, compared with a lower dose of melphalan and higher level of BNP (EFS: 15.0 months vs not reached, p=0.0166; OS: 15.0 months vs not reached, p=0.0166). No TRM was observed. Conclusions AL patients with less than 200 pg/ml of BNP can be safely performed HD-Mel with ASCT and expected longer survival. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
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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