Serum Immunoglobulin Free Light Chain in Primary Amyloidosis: Prognostic Value and Correlations with Clinical Features

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2733-2733
Author(s):  
Shaji Kumar ◽  
Angela Dispenzieri ◽  
Raynell Clark ◽  
Dirk Larson ◽  
Colin Colby ◽  
...  
Keyword(s):  
Overall Survival ◽  
Alkaline Phosphatase ◽  
Heavy Chain ◽  
Light Chain ◽  
Renal Involvement ◽  
Organ Involvement ◽  
Entire Group ◽  
Al Amyloidosis ◽  
Lower Serum

Abstract Background: Immunoglobulin free light chains (FLC) form the substrate for synthesis of amyloid fibrils in patients with AL amyloidosis. Development of FLC assay (Freelite) has allowed us to better assess the clonal cell burden in patients with AL amyloid. The relationship of the light chain types and their levels in serum to the clinical feature at presentation and the eventual outcome has not been systematically studied. Methods: We identified 730 patients with biopsy proven AL amyloidosis, who were seen at Mayo Clinic between January 1980 and July 2006, who were seen within 90 days of their diagnosis and in whom FLC levels were performed or had stored serum available for analysis. Cardiac biomarkers (cTnT, NT ProBNP) were also performed on stored serum for some of the patients as part of previous studies. Clinical data and follow up status are prospectively collected into the Dysproteinemia database, which was used for the study. Results: The median age of the study population was 63 years (range; 32–90) and 463 patients (63%) were male. The median estimated survival for the entire group was 37 months from diagnosis and the median follow up for the 263 patients (37%) alive at the time of the analysis was 27.8 months (range; 1–177 months). The plasma cell clone was lambda in 528 patients (72%) and kappa in 202 (28%) patients. The median absolute difference between the FLCs was 19.6 mg/dL for the entire group (range; 0.01–2478); for the kappa patients was 29.4 mg/dL (range; 0.01–1359) and for the lambda patients was 18.2 mg/dL (range; 0.03–2478). Kappa AL was associated with more involvement of the GI tract and liver as indicated by higher alkaline phosphatase (1.8 vs. 1.3 fold; P=0.03), higher total bilirubin (0.95 vs. 0.78 mg/dL, P = 0.04) and lower serum carotene (119 vs. 155 ug/dL; P = 0.0002). On the contrary, renal involvement was more in the lambda AL with the 24 hour urinary albumin higher in the lambda AL (2.4 gm vs. 1.4 gm; P = 0.0002) and lower serum albumin (2.77 vs. 2.97 mg/dL; P = 0.001). While there was no difference in the overall survival (OS) between the kappa and lambda AL, the median OS for those without a heavy chain was significantly shorter (12.6 months vs. 29.9 months; P= 0.01) compared to those with a heavy chain identified. There was also a correlation between high FLC difference and degree of organ involvement, especially cardiac. Among the 202 kappa AL patients, the median survival for those with a high FLC difference ( > 29.4 mg/dL) was 13 months vs. 48.8 months for those with low difference (P = 0.001). Similarly among the 528 patients with lambda AL, those with high difference (> 18.2 mg/dL) had a median OS of 9.3 months compared to 33 months for those with low difference (P < 0.0001) (Figure). The FLC difference was independent of the cTnT, NT Pro BNP, uric acid and fold-increase in alkaline phosphatase, all of which were significant in the multivariable analysis. Conclusions: The type of FLC impacts the spectrum of organ involvement, with gastrointestinal involvement observed more frequently with kappa, and renal involvement with lambda FLC. The FLC burden correlates with the degree of organ involvement, and is a significant predictor of overall survival in AL amyloidosis. Lambda FLC exerts similar effect as kappa FLCs, but at lower levels confirming the increased “amyloidogenicity” of lambda FLC. Finally, lack of a chaperone heavy chain is associated with a poorer outcome. Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC) Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC)

scholarly journals Improved Outcomes of Autologous Hematopoietic Cell Transplantation (AHCT) for Light Chain (AL) Amyloidosis: A Center for International Blood and Marrow Transplant Registry (CIBMTR) Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 193-193 ◽  
Author(s):  
Anita D'Souza ◽  
Baldeep Wirk ◽  
Mei-Jie Zhang ◽  
Jiaxing Huang ◽  
Amrita Krishnan ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Plasma Cell ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Renal Involvement ◽  
Organ Involvement ◽  
High Dose ◽  
Al Amyloidosis ◽  
Karnofsky Performance Score ◽  
Renal Response

Abstract Background: Light chain (AL) amyloidosis is a rare plasma cell neoplasm associated with systemic amyloid deposition leading to organ dysfunction and death without treatment. The use of AHCT in AL amyloidosis remains controversial as a prospective randomized control trial suggested inferior outcomes when compared with standard chemotherapy, driven primarily by high peri-transplant mortality (TRM) up to 24%. Improved patient selection criteria, supportive care and risk-adapted therapy have reduced TRM in recent single center studies. We analyzed trends and prognostic factors associated with AHCT outcomes in AL amyloidosis patients. Methods: We identified 1532 AL amyloidosis patients who underwent AHCT following high dose melphalan (MEL) within 24 months of diagnosis between 1995 and 2012 from the CIBMTR database. A subset of patients with more complete level of research data reported between 2001 and 2012 was analyzed for multivariate analysis (n=354). The primary endpoints were day30 and day100 mortality, hematologic progression free survival (PFS), hematologic relapse/progression and overall survival (OS). Data regarding cardiac, renal, hepatic and neurologic amyloid involvement was collected. Hematologic and organ response and progression were defined based on the 2004 uniform consensus criteria. Results: The median age at transplant was 57 years, with 61% males. AHCT was performed within 6 months of diagnosis in 66% patients. Karnofsky performance score (KPS) was <80 in 14%, HCT-CI was ≥ 3 in 20% and 69% had a lambda isotype. Organ involvement included renal, cardiac, hepatic and autonomic nervous system involvement in 74%, 38%, 16% and 11% respectively. Coexistent myeloma (>10% bone marrow plasma cells) was seen in 14%. Progressively higher numbers of patients received AHCT from 1995-2000 (n=140) to 2001-2006 (n=595) and 2007-2012 (n=800). The majority were untreated pre-transplant (77%) while 8% received melphalan, 6% thalidomide and 4% each received lenalidomide and bortezomib based pre-AHCT therapy. The median CD34 cell dose infused was 4.4 X 106/kg cells (IQR 3.3-6.2). MEL dose reduction was common (60% received < MEL 180 mg/m2 and 38% < MEL 140 mg/m2). The median length of hospital stay was 17 days (IQR 13-23). The median follow-up of patients from the time of transplant was 61 months (range 3-145). Day100 response included hematologic complete response, CR (12%), partial response, PR (26%), stable disease, SD (23%), and renal response (12%) with an ultimate best response of hematologic CR (33%), PR (28%), SD (19%) and renal response in 31%. Table 1 shows day30 and day100 mortality and OS at 1, 3 and 5 years showing steady declines in mortality rates and improvements in survival in successive time cohorts. Figure 1 shows the 5 year OS in each of the time cohorts. On multivariate analysis, albumin ≥ 3 g/dl at diagnosis, KPS ≥80, pre-transplant anti-plasma cell therapy and MEL ≥180 mg/m2 were associated with lower hematologic relapse/progression. KPS ≥80 and predominant renal involvement were associated with superior hematologic PFS while KPS ≥80 and < 2 organ involvement correlated with OS. Table 1 Outcomes of AHCT in AL amyloidosis. Values are expressed as probabilities with 95% confidence intervals. 1995-2000 N=140 2001-2006 N=595 2007-2012 N=800 Day 30 mortality 11 (7-17) 5 (4-7) 3 (2-4) Day 100 mortality 20 (14-27) 11 (8-13) 5 (4-7) 1 year survival 75 (67-82) 85 (81-87) 90 (88-92) 3 year survival 64 (56-72) 72 (68-75) 83 (80-86) 5 year survival 55 (46-63) 61 (57-65) 77 (72-82) Conclusions: There has been a significant improvement in survival of AL patients after AHCT driven primarily by a reduction in early peri-transplant mortality. Limited organ involvement, higher KPS, use of pre-transplant therapy and higher dose melphalan conditioning contributed to superior outcomes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Risk Of Progression Of Localised Amyloidosis To Systemic Disease In 606 Patients Over 30 Years

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3143-3143 ◽  
Author(s):  
Shameem Mahmood ◽  
Sajitha Sachchithanantham ◽  
Frank Bridoux ◽  
Thirusha Lane ◽  
Lisa Rannigan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Light Chain ◽  
Systemic Disease ◽  
Amyloid Deposition ◽  
Al Amyloidosis ◽  
Vital Organ ◽  
Organ Function ◽  
Research Support ◽  
Risk Of Progression

Abstract Localised AL (light chain) amyloidosis arises due to local formation and deposition of AL amyloid fibrils within a tissue. Little data exists as to the underlying aetiology, biological significance and natural progression of this disease. The primary objective of this study was to evaluate the incidence, clinical course, treatment outcomes and risk of progression to systemic disease. Methods This study included all patients with localised amyloidosis assessed at the UK National Amyloidosis centre between 1980 and 2011. Localised amyloidosis was defined as biopsy proven amyloid deposition confined to a single site without any evidence of vital organ involvement (including cardiac, renal, liver, peripheral or autonomic neuropathy) on detailed baseline assessment organ function and no visceral organ uptake on 123I serum amyloid P component (SAP) scintigraphy. Progression to systemic AL was defined as development of new vital organ involvement or dysfunction as by tests of organ function or SAP scintigraphy. Kaplan Meier curves were used to estimate the overall survival (OS); calculated from the start of diagnosis until death or last follow-up. Results Six hundred and six patients were diagnosed with localised amyloidosis, accounting for 12% of all newly diagnosed amyloidosis patients during this period at our Centre. The baseline characteristics are given in table 1. The median age was 59.5 years (range 48.8-68.6), 51% were male and median symptom duration was 7 months (range 4-24). All patients had biopsy proven amyloid deposition. Definitive light chain immunostaining for AL kappa or lambda was positive in only 15% while 52% had no immunostaining with antibodies to kappa, lambda, transthyretin or SAA. Three patients had ATTR on bladder biopsy (none with ATTR at other sites) and one with ApoA1 on laryngeal amyloidosis (with ApoA1 Ala164Ser mutation). The sites of localised amyloidosis included: bladder 94 (15%), lung 47 (7.7%), trachea-bronchial 35 (5.7%), larynx/vocal cords - 70 (11.6%), tonsil 4 (0.7%), conjunctiva 12 (2%), orbit 10 (1.7%), lymph nodes 31 (5.1%), GI tract 36 (6%), skin 54 (13.8%) and others. Presenting symptoms depended upon the tissue involved. A serum monoclonal protein was present in 12.5%, with an abnormal kappa/lambda ratio in 13.8%. Therapeutic options for localised disease include surgical procedures (36%), laser therapy (7%), steroids (2%), radiotherapy (2.8% predominantly for amyloidomas/symptom control) and chemotherapy (2.3%; treating amyloid symptoms/disease in 1%, treating co-existing multiple myeloma, lymphoplasmacytic lymphoma and MALT lymphoma in 1.3%). Some patients undergoing surgical procedures had recurrent local amyloid deposition needing repeated procedures. Only one patient out of 606 progressed to systemic AL amyloidosis. This patient presented with mediastinal LN involvement, progressed 5 years following diagnosis, with evidence of new uptake by 123I SAP scintigraphy localised within the spleen and bone marrow infiltration of 10% clonal plasma cells but no abnormal free light chain ratio or presence of a paraprotein. The majority of patients had other co-morbidities with the median age of death 74 years (range 66.5-80). There were no deaths due to progressive amyloidosis. The median follow up was 64 months. The median overall survival (OS) was 69.7 months (range 37.1-130.7) with 2 and 5 year OS 96% and 92% respectively figure 1. Conclusion The overall survival of localised AL amyloidosis is excellent and strikingly different from systemic AL amyloidosis. Treatment options are primarily directed locally to the amyloid deposit which is adequate in the majority, with less than satisfactory control and numerous procedures required in some patients, especially those with tracheobronchial amyloidosis, leading to a poor quality of life. Progression to systemic disease is an exceptionally rare occurrence even in presence of a detectable M-protein or abnormal light chain ratio. Disclosures: Bridoux: Janssen Cilag: Honoraria; Celgene: Honoraria; Celgene: Research Funding, Research support, Research support Other.

scholarly journals Similar Survival with Deferred Versus Salvage Autologous Stem Cell Transplant in Light Chain Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4579-4579 ◽  
Author(s):  
Danny Luan ◽  
Koen Van Besien ◽  
Paul J Christos ◽  
Roger Pearse ◽  
Danielle Guarneri ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Light Chain ◽  
Research Funding ◽  
Small Sample ◽  
Renal Amyloidosis ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant

Background: Light chain (AL) amyloidosis is characterized by deposition of misfolded monoclonal immunoglobulin light chains leading to organ dysfunction. AL amyloidosis has traditionally been treated with agents used in multiple myeloma, primarily alkylators, proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and high-dose melphalan/autologous stem cell transplantation (ASCT). A retrospective study comparing patients with AL amyloidosis who underwent ASCT as frontline therapy ('upfront ASCT') to those undergoing ASCT following induction ('deferred ASCT') revealed that deferred ASCT was associated with prolonged overall survival (OS) compared to upfront ASCT (Afrough et al, Biol Blood Marrow Transplant, 2018). Given the number of effective new therapies for AL amyloidosis, the potential to delay ASCT after one or more lines of therapy ('salvage ASCT') is feasible. To our knowledge, transplant outcomes of AL amyloidosis patients undergoing deferred vs salvage ASCT following at least one relapse have not been reported. A retrospective chart review was conducted to compare AL amyloidosis patients receiving deferred vs salvage ASCT for progression-free survival (PFS) and overall survival (OS). The study was approved by the Institutional Review Board at Weill Cornell Medical College. Methods: Twenty-four patients with AL amyloidosis who underwent deferred or salvage ASCT between 2000-2018 were included in the analysis. Patients who underwent upfront ASCT without induction chemotherapy were excluded. Demographics and clinical parameters were extracted from the electronic medical record. PFS was calculated from date of ASCT to first relapse and OS was calculated both from date of diagnosis and date of ASCT to death. Patients were censored if lost to follow-up prior to experiencing the relevant event. PFS as well as OS of patients who underwent deferred vs salvage ASCT were compared. Log-rank tests were used to statistically evaluate differences between Kaplan-Meier PFS/OS curves. Cox proportional hazards models were used to calculate hazard ratios (HR) using deferred ASCT as the reference treatment. Results: Among the 24 patients included in this analysis, 13 underwent deferred ASCT with 1 prior line of chemotherapy (e.g., induction), and 11 underwent salvage ASCT with a median of 3 prior lines (Table 1). Ten patients had cardiac amyloidosis, 15 had renal amyloidosis, and 6 had multi-organ involvement. Induction regimens received in the deferred group are included in Table 1. Neither PFS nor OS was significantly different between patients receiving deferred vs salvage ASCT. After median follow-up of 2.9 years, median PFS in patients who received deferred ASCT was 6.5 years and not reached in those who received salvage ASCT (P=0.47), with a HR of 1.74 (95% CI, 0.38-7.85) (Figure 1A). Median OS from date of ASCT was not reached in either group after a median follow-up of 2.8 years (P=0.52), with a HR of 2.16 (95% CI, 0.19-24.04) (Figure 1B). Similarly, median OS calculated from date of diagnosis was not significantly different between deferred vs salvage ASCT (P=0.79) (Figure 1C). Conclusions: In this cohort of 24 AL amyloidosis patients, no significant differences in PFS or OS were seen between patients undergoing deferred ASCT following induction vs salvage ASCT following multiple lines of therapy. Unlike the superior OS seen with deferred vs upfront ASCT, our findings show that either deferred or salvage ASCT may be associated with comparable outcomes and suggest similar OS despite timing of transplant. However, it is important to note the small sample size and that none of our patients received daratumumab-based regimens which may have improved PFS/OS in either or both groups. There were also small differences between groups in use of maintenance (1 vs 3 patients in the deferred and salvage groups, respectively) and proportion of patients receiving higher doses of melphalan 200mg/m2 vs 140 mg/m2 (69% vs 55% in deferred and salvage groups, respectively). Nevertheless, the lack of difference seen in PFS and OS between the two groups suggests that eventual hematologic relapse and organ progression with death occur at similar time intervals despite timing of ASCT. This speaks to the point that in newly diagnosed AL amyloidosis as well as later in the disease, achieving deep responses to prevent organ progression and death regardless of timing of ASCT remains an important treatment goal. Disclosures Van Besien: Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Pharmacyclics: Speakers Bureau; Merck: Research Funding; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health.

scholarly journals Quantitative Immunoprecipitation Free Light Chain Mass Spectrometry (QIP-FLC-MS) Simplifies Monoclonal Protein Assessment and Provides Added Clinical Value in Systemic AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4375-4375 ◽  
Author(s):  
Faye Amelia Sharpley ◽  
Hannah Victoria Giles ◽  
Richa Manwani ◽  
Shameem Mahmood ◽  
Sajitha Sachchithanantham ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Light Chain ◽  
Residual Disease ◽  
Renal Involvement ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Free Light Chains ◽  
Accurate Identification ◽  
Monoclonal Protein ◽  
Serum And Urine

Introduction Early diagnosis, effective therapy and precise monitoring are central for improving clinical outcomes in systemic light chain (AL) amyloidosis. Diagnosis and disease response assessment is primarily based on the presence of monoclonal immunoglobulins and free light chains (FLC). The ideal goal of therapy associated with best outcomes is a complete responses (CR), defined by the absence of serological clonal markers. In both instances, detection of the monoclonal component (M-component) is based on serum FLC assessment together with traditional serum and urine electrophoretic approaches, which present inherent limitations and lack sensitivity particularly in AL where the levels are typically low. Novel mass spectrometry methods provide sensitive, accurate identification of the M-component and may prove instrumental in the timely management of patients with low-level amyloidogenic light chain production. Here we assess the performance of quantitative immunoprecipitation FLC mass spectrometry (QIP-FLC-MS) at diagnosis and during monitoring of AL amyloidosis patients treated with bortezomib-based regimens. Methods We included 46 serial patients with systemic AL amyloidosis diagnosed and treated at the UK National Amyloidosis Centre (UK-NAC). All patients had detailed baseline assessments of organ function and serum FLC measurements. Baseline, +6- and +12-month serum samples were retrospectively analysed by QIP-FLC-MS. Briefly, magnetic microparticles were covalently coated with modified polyclonal sheep antibodies monospecific for free kappa light chains (anti-free κ) and free lambda light chains (anti-free λ). The microparticles were incubated with patient sera, washed and treated with acetic acid (5% v/v) containing TCEP (20 mM) in order to elute FLC in monomeric form. Mass spectra were acquired on a MALDI-TOF-MS system (Bruker, GmbH). Results were compared to serum FLC measurements (Freelite®, The Binding Site Group Ltd), as well as electrophoretic assessment of serum and urine proteins (SPE, sIFE, UPE and uIFE). Results Cardiac (37(80%) patients) and renal (31(67%) patients) involvement were most common; 25(54%) patients presented with both. Other organs involved included liver (n=12), soft tissue (n=4), gastrointestinal tract (n=3) and peripheral nervous system (n=2). Baseline Freelite, SPE, sIFE and uIFE measurements identified a monoclonal protein in 42(91%), 22(48%), 34(74%) and 21(46%) patients, respectively. A panel consisting of Freelite + sIFE identified the M-component in 100% of the samples. QIP-FLC-MS alone also identified an M-component in 100% of the samples and was 100% concordant with Freelite for typing the monoclonal FLC (8 kappa, 34 lambda). In 4 patients, QIP-FLC-MS identified an additional M-protein that was not detected by the other techniques. In addition, 4/8(50%) kappa and 4/38(11%) lambda patients showed a glycosylation pattern of monoclonal FLCs at baseline by mass spectrometry. Interestingly, the frequency of renal involvement was significantly lower for patients with non-glycosylated forms (25% vs 76%, p=0.01), while no similar relationship was found for any other organs. During the 1-year follow-up period, 17 patients achieved a CR; QIP-FLC-MS identified serum residual disease in 13(76%) of these patients. Conclusion In our series, QIP-FLC-MS was concordant with current serum methods for identifying the amyloidogenic light chain type and provided, against all other individual tests, improved sensitivity for the detection of the monoclonal protein at diagnosis and during monitoring. The ability to measure the unique molecular mass of each monoclonal protein offers clone-specific tracking over time. Glycosylation of free light chains is over-represented in AL patients which may allow earlier diagnosis and better risk-assessment of organ involvement. Persistence of QIP-FLC-MS positive M component in patients otherwise in CR may allow targeted therapy. Overall, QIP-FLC-MS demonstrates potential to be exploited as a single serum test for precise serial assessment of monoclonal proteins in patients with AL amyloidosis. Disclosures Wechalekar: GSK: Honoraria; Janssen-Cilag: Honoraria; Amgen: Research Funding; Takeda: Honoraria; Celgene: Honoraria.

scholarly journals Light chain type predicts organ involvement and survival in AL amyloidosis patients receiving stem cell transplantation

2018 ◽  
Vol 2 (7) ◽  
pp. 769-776 ◽  
Author(s):  
M Hasib Sidiqi ◽  
Mohammed A. Aljama ◽  
Eli Muchtar ◽  
Francis K. Buadi ◽  
Rahma Warsame ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Light Chain ◽  
Organ Involvement ◽  
Al Amyloidosis ◽  
Light Chain Type ◽  
Key Points ◽  
Λ Light Chain ◽  
Chain Type

Key Points λ Light chain AL amyloidosis is associated with a shorter PFS and OS compared with κ. Light chain type predicts likelihood of organ involvement in AL amyloidosis.

Larynx preservation after initial non-cisplatin containing combination chemotherapy plus radiotherapy, as opposed to surgical intervention with or without radiotherapy in previously untreated advanced head and neck cancer: final analysis after 12 years follow-up

1993 ◽  
Vol 107 (3) ◽  
pp. 211-216 ◽  
Author(s):  
L. A. Price ◽  
H. J. Shaw ◽  
Bridget T. Hill
Keyword(s):  
Overall Survival ◽  
Combination Chemotherapy ◽  
Median Overall Survival ◽  
Postoperative Radiotherapy ◽  
Local Therapy ◽  
Final Analysis ◽  
Entire Group ◽  
Larynx Preservation

After a median follow-up of 12 years, median overall survival of 73 patients with advanced squamous cell carcinoma of the larynx was 65 months. The 61 per cent of patients responding to two courses of initial schedule A combination chemotherapy, not including cisplatin, and the 81 per cent of patients achieving a final complete remission after definitive local therapy, had median overall survival figures of 95 and 97 months respectively. Overall survival and relapse-free survival in 51 patients treated with radiotherapy only with larynx preservation, were not significantly different from the 21 patients who completed their surgery with pre- or postoperative radiotherapy: median overall figures were 71 versus 65 months. These data add weight to our proposal that use of initial combination chemotherapy followed by radiotherapy may eliminate the need for radical surgery, so preserving the larynx in patients with advanced disease, and provides evidence of some long-term benefit with 32 per cent of this entire group surviving 12 years.

Cyclophosphamide, Bortezomib and Dexamethasone (CVD) Therapy in AL Amyloidosis Is Associated with High Clonal Response Rates and Prolonged Progression Free Survival,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3978-3978
Author(s):  
Christopher P. Venner ◽  
Julian D Gillmore ◽  
Thirusha Lane ◽  
Darren Foard ◽  
Lisa Rannigan ◽  
...  
Keyword(s):  
Renal Involvement ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Great Promise ◽  
Maximal Response ◽  
Al Amyloidosis ◽  
Effective Treatment Option ◽  
Free Survival ◽  
Entire Cohort

Abstract Abstract 3978 Background: Bortezomib alone and in combination with other agents has shown great promise in the treatment of AL amyloidosis in various preliminary open studies. Here we present our experience at the UK National Amyloidosis Centre with CVD in both the upfront and relapsed setting. Patients and Methods: The primary cohort comprises 37 patients referred to the National Amyloidosis Centre in London from 2006–2010. 27 patients had cardiac involvement by 2005 consensus criteria. 29 had renal involvement, 10 had liver involvement and 26 had other organs involved. Complete information for staging by the Mayo clinic criteria was available in 34 patients, and 47% were stage III based on values obtained prior to the initiation of CVD (23% of upfront patients and 62% of relapsed patients). The recommended CVD regimen was as follows: bortezomib 1.0 mg/m2 IV days 1, 4, 8, 11 (increase to 1.3 mg/m2 if well tolerated) cyclophosphamide 350 mg/m2 po days 1, 8, 15 dexamethasone 20 mg po days 1, 4, 8, 11 (increase to 40 mg if well tolerated) with an aim to deliver 6 cycles of treatment. Dose modifications were at the discretion of the treating haematologist. We aimed to assess response at 6 months (m). Haematologic and organ responses were defined as per the 2005 consensus criteria. The dFLC response (difference between the involved and uninvolved free light chain) was defined as the percent difference in the dFLC at the start of therapy and at response assessment and was considered assessable if the baseline dFLC was >50mg/L. A dFLC of 50–90% defined a partial response, and a dFLC of >90% defined a VGPR. Progression free survival (PFS) was calculated by the Kaplan-Meier method and calculated from the start of CVD until relapse, death or last follow-up. Statistical analysis was performed using SPSS version 19. Approval for analysis and publication was obtained from the institutional review board at the University College London, and written consent was obtained from all patients. Results: Median follow-up was 13.3m. Median time to assessment was 5.9m. Median number of cycles given was 4.9. All 37 patients were assessable by haematologic response criteria, 29 of whom were assessable for dFLC response. Overall hematologic response rate (RR) was 78.4% (CR = 35.1%). A VGPR was attained 48.3% of patients with an overall dFLC RR of 79.3%. 14 patients were treated with CVD upfront with a RR of 85.7% (CR = 64.3%, VGPR = 66.7%). 23 patients were treated in the relapse setting and the RR was 73.9% (CR = 17.4%, VGPR = 35.3%). Clonal response is detailed in table 1. 26 patients were assessable for a BNP response based on a pre-treatment NT-proBNP > 660 ng/L. BNP responses were seen in 8 patients (31%), stable disease in 14 (54%) and progression in 4 (15%). Of the entire cohort only one death was reported and there were no treatment related mortalities. The time to maximal response was 3.8m (3.0m and 3.8m in patients treated upfront and at relapse respectively). Median PFS has not been reached. The estimated 2-year PFS was 55.6% for the entire cohort, 69.6% for patients treated upfront and 43.8% for those treated at relapse. Attaining a CR correlated with a significant improvement in progression free survival compared with those who had not (median PFS not reached vs. 23.1m respectively, P = 0.029; figure 1A). Attaining a VGPR also correlated with an improved PFS compared with those who had not (median PFS not reached vs. 13.2m respectively, P = 0.003; figure 1B). Conclusion: This retrospective series lends further support to the use of bortezomib containing regimens in the treatment of AL amyloidosis. CVD is a safe and effective treatment option supporting similar findings in other small retrospective series, particularly when used in the upfront setting. This is, to our knowledge, the first series reporting PFS with this regimen. In addition, it confirms the importance of achieving a CR for improved survival outcomes and further validates the dFLC response as an important treatment endpoint. CVD is an attractive treatment combination for patients with AL amyloidosis many of whom are transplant ineligible due to advanced disease. Larger phase III studies are warranted and are underway. Disclosures: Wechalekar: Jansen Cilag: Honoraria.

Survival After Second, Third, and Fourth Line Therapy Better Than Expected in Patients with Previously Treated AL Amyloidosis Who Were Not Transplant Candidates At Diagnosis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 946-946 ◽  
Author(s):  
Girindra G Raval ◽  
Morie A Gertz ◽  
Martha Q Lacy ◽  
Suzanne R Hayman ◽  
Shaji K. Kumar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Time ◽  
Al Amyloidosis ◽  
Line Treatment ◽  
Second Line ◽  
Treatment Regimens ◽  
Line Therapy ◽  
Previously Treated ◽  
Better Than

Abstract Abstract 946 Background: The emerging therapies directed at the plasma cell clone have dramatically increased overall survival (OS) for both myeloma and amyloidosis patient populations. As more treatment trials are done in patients (pts) with AL, benchmarks for outcomes among previously treated AL pts are required, especially for those pts who are not candidates for high-dose chemotherapy with peripheral blood stem cell transplantation (ASCT). Inadequate information is available about the number of non-transplant pts who go on to receive second line treatment for AL amyloidosis. Methods: To ascertain the outcomes of pts who did not receive ASCT as primary therapy but who required a second line of therapy, we reviewed the experience of pts seen at Mayo Rochester between 1990 and 2010 according to an IRB approved retrospective review protocol. 1828 pts had their first Mayo visit for AL during this time period. Pts were excluded from this study for the following reasons: 571 had upfront transplant; 907 pts had received only one line of treatment for their amyloid; 91 had longstanding other associated malignancy [Waldenstrom's macroglobulinemia (8), lymphoma (15), CLL (6), multiple myeloma (62)]; and 93 had inadequate follow-up information. One-hundred and sixty-six pts received 2 or more lines of therapy for their AL amyloid and are the subject of these analyses. Statistical analyses were done using JMP statistical software (SAS, Carey, NC). Results: Of the 166 pts, the median age was 64 years (range 34, 84). 49% were male. Baseline organ involvement was as follows: cardiac 84/166 (50%); renal 118/166 (71); liver 23/166 (13.8%); peripheral nerves 19/166 (11.4%); and gastrointestinal 14/166(8.4%). Thirty-one percent (52/16) had both cardiac and renal involvement. Only 73 pts had cardiac biomarkers (NT pro BNP and Troponin T) done at baseline. Of these pts, 26% were stage 1, 49.3% were stage 2, and 24.6% were stage 3 according to original Mayo cardiac biomarker staging system. By inclusion criteria definition, all 166 pts received 1st and 2nd line therapies; 53 (32%) pts received 3rd line of treatment; 20 (12%) received 4th line of treatment; and 10 (6%) received 5th line of treatment. For first line therapy, the most common drugs given either singly or in combination were corticosteroid (147/166; 88.5 %), alkylator (99/166; 59.6%), IMID (34/166; 20.4 %), and bortezomib (19/166; 11.4%). The median time from diagnosis to 2nd line therapy was 10.3 months. Second line regimens received included: corticosteroid, 108/166 (65.1%); alkylator, 76/166 (45.8 %); IMID, 46/166 (27.7%); and bortezomib, 46/166 (27.8%). The median time from diagnosis to 3rd line therapy was 19.8 months. For the 53 pts who received 3rd line treatment, regimens included: corticosteroid, 41/53 (77.3%); IMIDs, 17/53 (32.1%); alkylator, 17/53 (32.1%); bortezomib, 12/53 (22.6%). The median time from diagnosis to 4th line therapy was 31.8 months. For the 20 pts receiving 4th line treatment, regimens included: corticosteroids, 15/20(75%); alkylator, 12/20 (60%), bortezomib, 7/20 (35%); and IMIDs, 4/20(20%). Eighty-three pts have died. The 1 year mortality of our study population was only 8%. The median follow-up of surviving pts was 47.6 months. Figure 1 demonstrates Kaplan-Meier estimates of overall survival (OS) from initiation of each successive therapy. The median OS from initiation of 1st, 2nd, and 3rd lines of treatment were 65, 49.5 and 36.7 months respectively. The median OS after the 4th line of treatment was not reached. The 4 year OS rates from initiation of 1st, 2nd, 3rd and 4th lines of therapy were 58%, 50.8 %, 50 % and 53.4% respectively. Conclusion: Outcomes among relapsed or refractory AL pts are better than what one might expect. Multiple publications have demonstrated that the 1 year mortality of newly diagnosed AL is in the vicinity of 40%. Thereafter, the rate at which pts die dramatically decreases. Our study provides explicit data characterizing the fate of pts unfortunate enough to require additional therapy but fortunate enough to survive past the exceedingly high risk period of death that occurs within 6–12 months of diagnosis. These data provide useful information for benchmarking future trials for treatments of AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

Autologous Stem Cell Transplantation In Immunoglobulin Light Chain Amyloidosis With Factor X Deficien

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2151-2151
Author(s):  
Stefan F Cordes ◽  
Morie A Gertz ◽  
Francis K Buadi ◽  
Yi Lin ◽  
Martha Q Lacy ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Stem Cell ◽  
Light Chain ◽  
Research Funding ◽  
Splenic Rupture ◽  
Al Amyloidosis ◽  
Factor X ◽  
Immunoglobulin Light Chain ◽  
Hemorrhagic Complications ◽  
Transient Improvement

Abstract Background Acquired factor X (FX) deficiency is associated with immunoglobulin light chain (AL) amyloidosis and may be accompanied by hemorrhage. There are limited data on the effects of autologous stem cell transplant (ASCT) on FX deficiency. We reviewed hemorrhagic complications and the effect of high dose melphalan (HDM) and ASCT on FX levels in AL amyloidosis patients with FX deficiency. Methods We conducted a retrospective chart review of patients with AL amyloid with FX levels below 60%, not on chronic anti-coagulation who underwent HDM/ASCT at the Mayo Clinic, Rochester, MN between 1995 and 2011. Results Forty-one of 358 patients (11%) met our study criteria. Median pre-ASCT FX was 45% (range: 2%, 59%). The most common bleeding complication was central line associated n=15 (37%) followed by gastrointestinal n=10 (24%) and genitourinary n=9 (22%). The most frequent and severe bleeding complications occurred in patients with FX levels less than 10%. Four patients required emergent splenectomy owing to splenic rupture; one of these patients died from hemorrhagic shock. Periprocedural prophylaxis included activated recombinant Factor VII (rFVIIa) infusions, fresh frozen plasma (FFP) infusions and platelet transfusions. rFVIIa was efficacious in controlling bleeding during splenectomy (n=5) and, in conjunction with arterial embolization, for retroperitoneal bleed (n=1). Elective splenectomy for FX deficiency (n=1) resulted in only transient improvement in FX level. No relationship between the degree of pre-ASCT FX deficiency and other laboratory values (alkaline phosphatase, AST, total bilirubin, serum albumin, total serum protein, serum creatinine, total urine protein, beta2 microglobulin, troponin T) was found. Post-ASCT FX levels were determined in seventeen patients. In four of these patients, post-ASCT FX levels were determined in the acute/subacute phase of ASCT before steady state FX levels could be achieved; the median change in FX for these patients was -6.5% (range: -19%, 3%). In the remaining thirteen patients, who were between 99 and 1920 days from ASCT, FX improved by median 26% (range: -15%, 92%). Overall post-ASCT FX increased in twelve of thirteen (92%) patients. The improvement in FX correlated with improvement in the degree of proteinuria (p = 0.04) and showed a trend towards significant correlation with improvement in serum alkaline phosphatase (p = 0.06). Conclusions Hemorrhagic complications are most frequent and severe for FX levels below 10%. rFVIIa infusions, FFP and platelets were effective prophylactic agents. In the single patient who underwent elective splenectomy, a transient improvement in FX level was seen. Splenectomy was otherwise reserved for patients with splenic rupture/hematoma. Post-ASCT FX levels increased in twelve (92.3%) of the remaining thirteen patients; five of the patients (38.5%) were no longer FX deficient after ASCT. The degree of improvement in FX levels was correlated with improvement in markers of renal or hepatic involvement by amyloid. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

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