Systemic Light Chain Amyloidosis Research Articles

Amyloid in bone marrow smears in systemic light-chain amyloidosis

We performed a prospective sensitivity analysis to detect amyloid in bone marrow (BM) smears stained with Congo red (CR) and according to Pappenheim of patients with systemic light-chain (AL) amyloidosis. Results were directly compared to routine BM histology and fat aspiration. We analysed 198 BM smears from patients with the diagnosis or suspicion of systemic AL amyloidosis. Ultimately, the diagnosis could be established for 168 patients. Amyloid was detected on BM smears with CR in 33% (56/168). All patients suspicious for amyloid on Pappenheim staining (n = 39) showed substantial amyloid infiltration on CR. No patient without systemic AL amyloidosis stained positive. Sensitivity for routine BM histology was 57% (74/129) and for fat aspiration 96% (134/140). Patients with amyloid on BM smears had significantly more hepatic (42 vs. 9%, p < .001), renal (78 vs. 43%, p < .001) and gastrointestinal involvement (40 vs. 22%, p < .01) and less commonly cardiac involvement (58 vs. 76%, p < .03) and consecutively no adverse prognosis. CR staining of BM smears cannot be recommended as a primary screening tool for systemic AL as its overall sensitivity is far inferior to BM histology and fat aspiration. However, we recommend using the technique when suspecting amyloid on Pappenheim staining to establish the diagnosis of systemic AL amyloidosis.

Prevalence and prognostic impact of left-sided valve thickening in systemic light-chain amyloidosis.

Left heart valve thickening (LVT) was described in patients with light-chain amyloidosis (AL). This phenomenon reflects likely infiltration of the valve by amyloid proteins. However, the prevalence of LVT and its prognostic value have not been investigated in patients with AL. Comprehensive transthoracic echocardiography was performed at baseline in 150 patients [median age 68 (33-87) years; 59% male] with confirmed AL. The presence of abnormal mitral and/or aortic valve thickening (>3mm) was assessed in all included patients. Overall, 42% had LVT at the time of diagnosis. Compared to patients without LVT, those with LVT were older and had a more advanced NYHA functional class (63% in patients with NYHA III-IV vs. 33% in NYHA I-II, p<0.001). They also had higher left ventricular (LV) wall thickness and mass, larger left atrium, higher mitral annulus E/E' ratio and systolic pulmonary artery pressures, and lower LV ejection fraction (all p<0.05). Patients with more advanced Mayo Clinic stage had a higher incidence of LVT: 58% in stage III vs. 45% in stage II and 5% in stage I (p<0.001). During a median follow-up of 2years, 79 deaths occurred. The presence of LVT was significantly associated with reduced 5-year survival (32±7 vs. 64±6%). In multivariate analysis, after adjusting for age, gender, NYHA functional class, and LV ejection fraction, LVT remained significantly associated with higher all-cause mortality (hazard ratio 1.90, 95% CI 1.10-3.34, p=0.02). Left heart valve thickening is common in patients with AL and is associated with worse functional class, LV systolic and diastolic function, and more advanced stage of the disease. In addition, LVT appears to be a powerful marker of all-cause mortality.

Patterns of Treatment Failure in Systemic Light Chain Amyloidosis with Long-Term Survival after Chemotherapy

BackgroundThe prognosis of systemic light chain (AL) amyloidosis is poor, which is associated early death assiated with cardiac involvement. It was reported that patients who avoided earth death have better survival than myeloma patients. However, the patterns of treatment failure of AL amyloidosis patients with long-term survival have not been evaluated. The aim of this study was to analyze the clinical outcome of patients with AL amyloidosis who survived more than 1 year and experienced treatment failure after systemic chemotherapy.MethodsIn this retrospective cohort study, 165 patients with AL amyloidosis received chemotherapy including ASCT in Samsung medical center between September 1997 and September 2015 were analyzed. The conditioning chemotherapy of ASCT was high-dose melphalan (200mg/m2). The patients who survived more than 1 year and showed disease progression or death were included in the study population. Progression was defined as first hematologic or organ progression after diagnosis of systemic amyloidosis. Hematologic or organ progression was evaluated according to the Roundtable on Clinical Research in Immunoglobulin Light-chain Amyloidosis. The progression-free survival and overall survival were analyzed.ResultsA total of 112 patients who survived more than 1 year during the study period with median follow-up 50.3 months, 7 patients was lost to follow-up and 47 patients did not showed progression. 58 patients experienced death or progression and they were eligible for analysis. 14 of 58 (24.1%) patients received ASCT, 13 (22.4%) patients received bortezomib-based regimens, 6 (10.3%) patients received oral melphalan with dexamethasone before progression. 4 (6.9%) patients achieved hematologic complete remission (CR) and 5 (8.6%) patients achieved hematologic very good partial response (VGPR), all of 9 patients demonstrated cardiac progresion. Otherwise, 27 of 47 patients (57.4%) without progression achieved hematologic CR or VGPR. Among 54 patients who did not achieve hematologic CR, 24 (44.4 %) patients showed hematologic progression and 28 (51.9%) patients showed cardiac progression, kidney progression was 17 (31.5%) and liver progression was 3 (5.6%), respectively. There were 4 patients with hematologic progression followed by cardiac progression, and the median time interval from hematologic progression to cardiac progression was 2.6 months. 39 deaths (67.2%) were identified in cohort and most common cause of death was cardiac progression (12 of 39 deaths - heart failure, fatal arrhythmia, cardiac arrest).ConclusionMore than half of patients in this cohort received ASCT or bortezomib based chemotherapy, cardiac progression was a leading cause of treatment failure in systemic AL amyloidosis with long-term survival (>1 year), even in the patients with hematologic CR. Continuation of chemotherapy or ASCT beyond hematologic response might be needed to achieve cardiac response and long-term survival in patients with AL amyloidosis who demonstrated cardiac progression. Further studies to elucidate the efficacy of chemotherapy beyond hematologic response are warranted. DisclosuresNo relevant conflicts of interest to declare.

Bortezomib Versus Non-Bortezomib Based Treatment for Transplant Ineligible Patients with Light Chain Amyloidosis

Introduction: Chemotherapeutic options for patients with systemic light chain amyloidosis (AL) who are not transplant candidates include bortezomib based therapy, melphalan with dexamethasone, and less commonly, immunomodulatory drugs (IMiDs). However, prospective clinical trial data comparing these regimens are lacking. This study aims to compare efficacy of bortezomib-based treatment to other therapies.Methods: All patients with AL seen within 90 days of diagnosis at our institution over a 10-year period (2006 to 2015) who did not undergo a stem cell transplant were identified from our institutional database. Data pertaining to demographics, diagnosis, treatment and follow-up were extracted from electronic medical records. Analyses were carried out by chi-square and Fisher's exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Progression free survival (PFS) is defined as time to death, progression requiring treatment change or relapse requiring re-institution of treatment. PFS and overall survival was analyzed via the Kaplan-Meier method.Results: Seven hundred and twenty five patients met the inclusion criteria, of which 38% (n=275) received bortezomib containing regimens and 62% (n=450) received non-bortezomib based therapies. Bortezomib was used with dexamethasone in 24% (n=67) patients; and with other drugs, most commonly cyclophosphamide, in 76% (n=208) patients. Non-bortezomib treatment regimens included melphalan-based treatment in the majority (92%, n=414) followed by IMiDs with steroids and other drugs (8%, n=36). Baseline variables similar in both groups and their distribution in the entire cohort was as follows: gender distribution (63.3% males, n=459), median age of diagnosis (66.3 years, range 32.2 to 93.6), type of involved free light chain (FLC) (lambda 73%, n=523) and median plasma cell burden (10%, range 0 to 91). Median difference between the involved and uninvolved free light chain (dFLC) was higher in the bortezomib group (29 mg/dL vs. 23 mg/dL; p=0.017). There was no difference in organ involvement. In the bortezomib group, organ involvement was as follows: cardiac (81%, n=219), renal (62%, n=168) and hepatic (18%, n=48). In the non-bortezomib group, the rates of organ involvement were similar: cardiac (78%, n=346), renal (57%, n=247) and hepatic (19%, n=85).Median duration of first line treatment was similar in the 2 groups, with 178 days in the bortezomib cohort and 187 days in the non-bortezomib cohort.Response rates are illustrated in Table 1. Rates of very good partial response (VGPR) or better response were higher in the bortezomib group (64 % vs. 54%, p=0.0002). Patients treated with bortezomib achieved VGPR faster with higher rates of VGPR or better response seen at 3 months (48% vs. 27%, p <0.0001) and 6 months (57% vs. 34%, p < 0.0001) after initiation of therapy compared to non-bortezomib treatment. Rates of organ response were similar amongst the 2 groups as shown in Table 1. However, median time taken to achieve a cardiac response was shorter in the bortezomib group (23 vs. 38 weeks, p=0.0026). In a multivariable model, bortezomib-based treatment and dFLC at diagnosis were predictors of VGPR.Relapse or progression requiring change in therapy was more common in patients treated with non-bortezomib based therapy (38%, n=143/372) compared to bortezomib-based treatment (28%, n=67/236); p =0.01). However, no difference in overall survival was observed in patients treated with bortezomib (2.2 years; 95% confidence interval (CI): 1.7 to 3.3) vs. non-bortezomib therapies (1.7 years; 95% CI: 1.3 to 2.5).Conclusion: Treatment with bortezomib-based regimens results in a deeper response including higher rates of early VGPR at 3 and 6 months from starting therapy. Moreover, these patients achieve cardiac response faster and have lower rate of relapse. However, no difference in overall survival was seen, which may be explained by subsequent use of bortezomib-based therapies in this population. [Display omitted] DisclosuresDispenzieri:Celgene: Research Funding; Alnylam: Research Funding; pfizer: Research Funding; Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Kumar:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

Treatment Patterns and Clinical Outcomes Among Patients with Newly Diagnosed and Relapsed/Refractory Systemic Light Chain Amyloidosis

OBJECTIVES:The prognosis for light chain amyloidosis (AL) is generally poor, particularly with cardiac, renal and multi-organ involvement. Treatment options for patients with relapsed/refractory light chain amyloidosis (RRAL) are limited. There is also a shortage of real-world evidence of treatment patterns and comparative effectiveness of treatment regimens for RRAL. The aims of this study were to describe treatment patterns in patients with newly diagnosed AL or RRAL, including types of treatment lines, as well as duration of treatment. Additionally, we aimed to characterize the incidence of vital organ (heart and kidney) deterioration and mortality following second-line or later-line treatment.Methods:This is a retrospective observational study of adult patients with AL using US Optum administrative claims data during 1/1/2008 to 6/30/2015. AL diagnosis was based on both the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes (277.30 or 277.39) and treatments with a claim for AL-specific anticancer systemic agents. AL patients who received stem cell transplantation (SCT) only without other AL-specific anticancer agent were not included. Patients who had claims for AL, in addition to another primary cancer or metastatic disease during the 12-month wash-out period were excluded. Patients receiving a second line of treatment for AL were classified as RRAL. Clinical outcomes included mortality and hospitalizations due to cardiac or renal deterioration. Health care resource utilization during one year following RRAL was reported by per patient per month.RESULTS:A total of 334 patients were identified with AL (Figure 1). The average age of AL patients was 66 years with a range of 23-88 years (Table 1). Based on prior therapies, 144 (43.1%) out of 334 patients were considered as RRAL. Majority (108/144) of the RRAL patients had evidence of cardiac or renal disease before the second line treatment.Over one third of the patients received monotherapy, and approximate half received doublet therapy for both first line AL and RRAL patients. Proteasome inhibitor (PI) based regimens were the most frequently used (41.0% for first-line AL, 30.6% for RRAL) followed by regimens based on immunomodulatory agents (15.0% for first-line AL, 28.5% for RRAL), alkylating agents (19.8% for first line AL, 14.6% for RRAL) and other combinations. SCT was part of the treatment regimen in 7.2% of first-line AL patients, and 12.5% of RRAL. Patients who received AL treatment with PI as first-line had higher reported occurrence of baseline (at initial diagnosis) heart failure (48.0% vs 30.9%), cardiomyopathy (41.4% vs 23.5%), and renal disease (57.6% vs 46.3%) compared to non-PI treated patients (p<0.05 for all). For patients who had cardiac or renal involvement, as shown in Table 2, 49.3% had organ deterioration during the two years following relapse, including mortality (10.4%), heart failure (28.4%), cardiomyopathy (16.4%), dialysis (7.5%) and pulmonary edema (1.5%). During the first year following relapse, the average healthcare resource utilization per patient per month included 0.16 inpatient admissions (0.07 due to cardiomyopathy/renal disease complications), 3.02 outpatient or office visits, 0.14 emergency room visits, and 0.05 intensive care unit admissions; and the average length of stay for inpatient admission was 8.2 days.CONCLUSIONS:In this real-world cohort study of patients with AL, majority of patients had cardiac or renal involvement at the start of RRAL treatment. PI regimens are the most common treatment in both 1st line and 2nd line. PI-based regimens were chosen in patients with worse clinical characteristics prior to the treatment, likely because of the perceived need in these patients for the rapid and deep free light chain responses which can be generated by PI-based therapies. Clinical outcomes remained poor emphasizing the need for medications to improve care for patients with RRAL. [Display omitted] [Display omitted] [Display omitted] DisclosuresLin:Takeda: Employment. Asche:Takeda: Consultancy. Ren:Takeda: Consultancy. Yong:Takeda: Employment. Parameswaran:Takeda: Consultancy. Luptakova:Takeda Oncology: Employment. Faller:Takeda: Employment. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership.

Risk-Adapted Melphalan and Stem Cell Transplantation after Suboptimal Responses to Bortezomib-Based Initial Therapy in Patients with Systemic Light-Chain Amyloidosis (AL)

The treatment of newly diagnosed patients with AL has dramatically improved with the use of the first-in-class proteasome inhibitor bortezomib in initial therapy (Kastritis et al., Haematologica, 2007). Overall hematologic response rates of 62% have been reported in a large series with 43% of patients achieving very good partial (VGPR) or complete responses (CR), i.e.> VGPR (Palladini et al., Blood, 2015). In fact, bortezomib-based therapy is now commonly used as front-line treatment in lieu of transplant or as cytoreduction prior to ASCT. However, patients who have suboptimal hematologic responses such as partial or no response (PR, NR) to bortezomib-based therapy are likely to have inferior overall survival (Palladini et al., JCO, 2012). The clinical efficacy of risk-adapted melphalan (MEL) and autologous stem cell transplantation (ASCT) as a second-line option for such patients has not been formally studied.We report on 12 patients, 8 men and 4 women with a median age of 58 (range, 53-70) with suboptimal responses to initial therapy who were referred for and underwent ASCT after a median of 4 cycles of bortezomib-based therapy (range, 2-8). Eight patients had NR with median involved FLC values at diagnosis and post initial therapy/pre-SCT of 180 (74-648) and 265mg/L (116-410) respectively while 4 had PR with medians of 1401 (250-9750) and 94mg/L (43-1620); in neither case were comparisons significant by paired t-test. Seven patients had 2 organs involved and 5 had one. Eight patients had cardiac involvement, seven stage 2 and one stage 3. Six patients had renal involvement, one stage 1, four stage 2, and one stage 3. Two had GI involvement.All patients were mobilized successfully with filgrastim and plerixafor as previously described (Kaul et al., BMT, 2014). A median of 9.8 x 106 CD34+ cells/kg (range, 5.4-23.3) were collected. All patients received melphalan at doses of 200 mg/m2 (4 patients, 33%), 140 mg/m2 (7 patients, 58%), and 100 mg/m2 (1 patient, 8%). A median of 6.6 x 106 CD34 cells/kg (4.5-14.0) were infused. All patients engrafted and all had their post-SCT hematologic responses assessed. There was one treatment-related death at 2 months post-SCT in a 70 year old woman who had stage 2 cardiac and stage 2 renal disease, received MEL 100 mg/m2 and had improved her hematologic response status from NR to PR. Overall post-SCT, 75% of patients achieved > VGPR including 42% who achieved CR (n=5). Eight patients have received consolidation with bortezomib and/or lenalidomide based regimens, with four patients achieving CR. Two patients are about to start consolidation. With a median follow-up of 27 months (1-42), two renal and four cardiac responses have been achieved. Median overall survival post-SCT has not been reached (Figure).In conclusion, risk-adapted melphalan and ASCT is a safe, feasible, timely and effective second-line therapy for patients with AL who have suboptimal responses to bortezomib-based initial therapy. [Display omitted] DisclosuresComenzo:Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Karyopharm: Research Funding.

Treatment Patterns and Outcomes Following Initial Relapse in Patients with Relapsed Systemic Immunoglobulin Light Chain Amyloidosis

IntroductionImmunoglobulin light chain amyloidosis (AL Amyloidosis) is a plasma cell disorder characterized by deposition of misfolded insoluble protein fibrils (composed of monoclonal κ or λ light chains) in tissues causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT), when eligible, are standard treatment options but relapses remain inevitable for most patients. However, there is a paucity of literature describing relapsed or refractory patients. We performed a retrospective study to analyze the outcomes upon relapse and the impact of type of therapy and retreatment with the same therapy at relapse.MethodsClinical and laboratory data of 1327 consecutive patients with systemic AL amyloidosis seen at Mayo Clinic within 90 days of their diagnosis, between 2006 and 2015, was collected by chart review and analyzed retrospectively. Of these patients, 219 (16.5%) were lost to follow-up. Among the remaining 1108 patients, 366 patients experienced a documented hematological or organ relapse or progression requiring change of first line or start of second line therapy and form the current study population. Overall survival (OS) was calculated from start of second line treatment or progression mandating therapy until death from any cause or the date of last follow up. The OS was estimated using the Kaplan-Meier method and log rank test was used to estimate the difference in survival curves.ResultsThe median age was 62.8 years (36.1 - 85.3); 63.1% were males; 64.7% / 59.3% / 11.4% had cardiac / renal / hepatic involvement and 24.2% / 32.1% / 23.3% / 20.3% had MS I/II/III/IV.The median estimated follow up for this cohort was 69.4 months (95% CI; 64.4, 76.8) from the start of first line therapy and 45.2 months (95% CI; 36.5, 50.6) from the start of second line therapy or progression requiring treatment. The median time to second line treatment or relapse /progression mandating therapy was 16.2 months (1-93) from the start of first line therapy. At relapse, 14 patients underwent ASCT, 165 were treated with proteasome inhibitor (PI) based therapy, 83 with immunomodulator (IMiD) based therapy, 33 with alkylator based therapy, 15 with a combination of PI and IMiD, 10 with steroids, 8 with other therapies and 38 did not receive treatment.Among the 366 patients, 124 (33.9%) required change or reinstitution of therapy during follow up at the time of analysis. The median time to third line treatment or relapse /progression mandating therapy was 31 months (95% CI; 24, 40.5) from the start of second line treatment. The median overall survival (OS) was 76.4 months (95% CI; 65.2, 83.6) from the start of first line therapy and 38.8 months (95% CI; 29.6, 52.6) from the start of second line therapy.The type of therapy at relapse (ASCT vs PI vs IMiD vs melphalan vs steroids and others) did not alter the time to next therapy (ASCT, 43.1m; PI, 31m; IMiD, 37m; melphalan, 20.8m; steroids and others, 20m; p=0.3) and OS (ASCT, 66.9m; PI, 51.1m; IMiD, 51.3m; melphalan, 37.2m; steroids and others, 80.7m; p=0.9) from the start of the second line treatment; as depicted in Figure 1. Retreatment with a different drug class (as the first line treatment) at relapse significantly reduced the time to next treatment (32.3m vs 22 m; p= 0.01) as compared to same therapy; but did not have any impact on survival (30.8m vs 51.1m; p = 0.5); as presented in Figure 2.ConclusionThis study provides novel information about outcomes of patients with systemic AL amyloidosis who relapse or progress after first line therapy which could be useful in planning salvage therapies and designing clinical trials. Retreatment with a different therapy at relapse improves time to next therapy but does not impact OS. Hence, we conclude that the patients can fare well post relapse/ progression and can benefit from various treatment regimens including retreatment with the same agent. [Display omitted] [Display omitted] DisclosuresDispenzieri:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; pfizer: Research Funding; Alnylam: Research Funding; Celgene: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding.

Final Results of a Phase 2 Study of Bendamustine in Combination with Dexamethasone in Patients with Previously Treated Systemic Light-Chain (AL) Amyloidosis

Background: No established therapies exist for patients who fail or relapse after initial therapy for AL amyloidosis. Bendamustine has shown potential in treating multiple myeloma, chronic lymphocytic leukemia and non-Hodgkins lymphoma but it has not been well studied in AL amyloidosis. We sought to investigate the efficacy and safety of using Bendamustine in combination with dexamethasone (Ben/Dex) in patients with relapsed AL amyloidosis in a multi-center phase 2 study and present the results of the final analysis.Methods: This Phase IIa clinical trial enrolled 31 patients who had persistent or progressive AL amyloidosis after at least 1 prior therapy. An optimal two-stage Simon design approach was used. Of 13 patients initially enrolled, 3 experienced hematologic partial response (PR), and an additional 16 were treated in the second stage. It was pre-determined that if 9 or more of the 29 patients with evaluable response had hematologic PR or better the treatment would be considered worthy of further development. Evaluable response was defined as patients who completed at least 2 treatment cycles. The primary objective was to determine the rate of partial hematologic response (PR). Secondary objectives included the overall hematologic response rate, organ response rate, toxicity profile, event free survival, and overall survival (OS). Patients received treatment in 28 day cycles with Bendamustine given on day 1 and day 2 (100 mg/m2 IV for CrCl≥60 mL/min, 90 mg/m2 IV for CrCl 59-30 mL/min, 70 mg/m2 IV for CrCl 15-30 mL/min) and dexamethasone 20-40 mg given weekly. Treatment was continued until disease progression or for up to 6 courses after complete response (CR). Reasons for discontinuation also included unacceptable toxicity, patient refusal, and non-response.Results:Of the 31 patients enrolled in the trial, 29 had evaluable responses and completed a median of 4 cycles of therapy (range 2-12) with one patient still undergoing treatment as of 7/1/2016. Median age of enrolled patients was 64 (range 42-78). Primarily involved organs included heart (53%), kidney (36%), nerve (7%), and liver (4%); 18 patients had ≥2 major organs involved. The patients received a median of 1.5 prior treatments (range 1-4) and 13 had received prior autologous stem cell transplants. Of evaluable patients (n=29), 41% had hematologic response to Ben/Dex (3% CR, 17% very good partial response, 24% PR). Of these 13 patients, 6 had a response after only 1 cycle of therapy and the median time to best response was 1 cycle (range 1-6 cycles). The median follow up of patients was relatively long, 18.4 months (range 1.5-41.5) and the median OS has not yet been reached (Figure 1). Event free survival defined as time to death, progression of disease or initiation of new therapy was 9.24 months (range 1.8-18.0) (Figure 2). Only 3 patients discontinued treatment due to disease progression while 8 stopped due to an adverse event (AE) although 5 AEs were only grade 1-2 events. There was 1 death during treatment that was unrelated to the study drug and due to underlying cardiac amyloidosis. The most common drug related all grade AEs included anemia (9%), fatigue (8%), and nausea (7%). Organ response was observed in 5 out of 16 patients with renal involvement and 2 out of the 19 patients with cardiac involvement.Conclusions: Bendamustine in combination with dexamethasone is active treatment in patients with AL amyloidosis who had failed multiple prior therapies and results in a significant hematologic response. Treatment was very well tolerated with a low incidence of severe AE in this delicate patient population. Therefore bendamustine is another treatment approach for AL amyloidosis patients who currently have limited therapeutic options. [Display omitted] [Display omitted] DisclosuresLentzsch:Foundation One: Consultancy; BMS: Consultancy; Celgene: Consultancy, Honoraria. Comenzo:Karyopharm: Research Funding; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Zonder:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Pregja:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pharmacyclics: Other: data safety monitoring committee. Landau:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy.

Safety and Efficacy of Carfilzomib (CFZ) in Previously-Treated Systemic Light-Chain (AL) Amyloidosis

Safety and Efficacy of Carfilzomib (CFZ) in Previously-Treated Systemic Light-Chain (AL) Amyloidosis

Regional differences in prognostic value of cardiac valve plane displacement in systemic light-chain amyloidosis

BackgroundTo compare the prognostic value of cardiac valve plane displacement (CVPD) on various locations in cardiac light chain (AL) amyloidosis.MethodsConsecutive patients with biopsy-proven cardiac involvement in AL amyloidosis who had undergone cardiovascular magnetic resonance (CMR) between 2005 and 2014 in our institution, were retrospectively identified and data analyzed. The primary combined endpoint was all-cause mortality or heart transplantation. Systolic CVPD were obtained from standard cine bSSFP in 2-, 3- and 4-chamber views at anterior aortic plane systolic excursion (AAPSE); anterior, anterolateral, inferolateral, inferior, inferoseptal mitral (MAPSE); and lateral tricuspid (TAPSE) annular segments.ResultsWe identified 68 patients (58 ± 10 years; 59% male). Median follow-up period was 1.2 years (IQR, 0.3-4.1). Significant differences in CVPD between patients who reached a primary endpoint (n = 44) and transplant-free survivors were found only for AAPSE (6.1 mm (IQR, 4.6-9.4) vs. 8.8 mm (IQR, 6.9-10.4); p = 0.02) and MAPSEanterolateral (7.3 mm (IQR, 5.4-11.7) vs. 10.5 mm (IQR, 8.1-13.4); p = 0.03). AAPSE (χ2 = 15.6; p = 0.0002) provided the best predictive value for transplant-free survival compared to all other valvular plane locations. A high-risk cutoff (AAPSE ≤ 7.6 mm) was calculated by ROC analysis to predict all-cause death or heart transplantation within 6 months from index examination (AUC = 0.80; CI: 0.68 to 0.89; p < 0.0001). AAPSE added incremental prognostic power to an imaging prediction model of late gadolinium enhancement and global longitudinal strain (GLS) (∆χ2 = 5.8, p = 0.02) as well as to a clinical model including Karnofsky index and NT-proBNP (∆χ2 = 6.2, p = 0.01).ConclusionIn patients with cardiac involvement in AL amyloidosis, systolic CVPD obtained from standard long axis cine views appear to indicate outcome better, when obtained in the anterior aortic plane (AAPSE) and provide incremental prognostic value to LGE and strain measurements.

Progressive refractory light chain amyloidosis and multiple myeloma patients are responsive to the addition of clarithromycin to IMiD based therapy.

Multiple myeloma (MM) and primary systemic light chain amyloidosis (AL) are both chronic plasma cell dyscrasias with different clinical expression but limited treatment options for relapsed refractory disease. We report the effect of the addition of clarithromycin on 31 MM and 17 AL with relapsed or refractory disease who had an insufficient response or disease progression while on an IMiD based therapy. In this high risk population, hematological response was reported in 48% of MM patients and 94% of AL patients. Responses were reported early in both groups (median 35 days) and were more sustained in AL patients. Adverse events were common and included mostly grade 1-2 fatigue, infections and abdominal discomfort. Cytopenias were common and cardiac complications were rare in both MM and AL patients. Clarithromycin-IMiD combination therapy appears to be both effective and safe in progressive MM and primarily in AL patients, although a prospective clinical trial is warranted to validate these results. Am. J. Hematol. 92:131-135, 2017. © 2016 Wiley Periodicals, Inc.

PCN184 - Healthcare Cost and Utilization Among U.S. Patients with Relapsed/Refractory Systemic Light Chain Amyloidosis (RRAL)

PCN184 - Healthcare Cost and Utilization Among U.S. Patients with Relapsed/Refractory Systemic Light Chain Amyloidosis (RRAL)

Anterior Aortic Plane Systolic Excursion: A Novel Indicator of Transplant-Free Survival in Systemic Light-Chain Amyloidosis

Anterior aortic plane systolic excursion (AAPSE) was evaluated in the present pilot study as a novel echocardiographic indicator of transplant-free survival in patients with systemic light-chain amyloidosis. Eighty-nine patients with light-chain amyloidosis were included in the post-hoc analysis. A subgroup of 54 patients with biopsy-proven cardiac amyloid infiltration were compared with 41 healthy individuals to evaluate the discriminative ability of echocardiographic findings. AAPSE is defined as the systolic excursion of the anterior aortic margin. To quantify AAPSE, the M-mode cursor was placed on the aortic valve plane in parasternal long-axis view at end-diastole. Index echocardiography had been performed before chemotherapy. Median follow-up duration was 2.4years. The primary combined end point was heart transplantation or overall death. Mean AAPSE was 14±2mm in healthy individuals (mean age=57±10years; 56% men; BMI=25±4kg/m2). AAPSE<11mm separated patients from age-, gender-, and BMI-matched control subjects with 93% sensitivity and 97% specificity. Median transplant-free survival of patients with AAPSE<5mm was 0.7 versus 4.8years (P=.0001). AAPSE was an independent indicator of transplant-free survival in multivariate Cox regression (echocardiographic model: hazard ratio=0.72 [P=.03]; biomarker model: hazard ratio=0.62 [P=.0001]). Sequential regression analysis suggested incremental power of AAPSE as a marker of transplant-free survival. An ejection fraction-based model with an overall χ2 value of 22.8 was improved by the addition of log NT-proBNP (χ2=32.6, P<.005), troponin-T (χ2=39.6, P<.01), and AAPSE (χ2=54.0, P<.0001). AAPSE is suggested as an indicator of transplant-free survival in patients with systemic light-chain amyloidosis. AAPSE provided significant incremental value to established staging models.

Systemic Immunoglobulin Light Chain Amyloidosis–Associated Myopathy: Presentation, Diagnostic Pitfalls, and Outcome

ObjectiveTo characterize the natural history of immunoglobulin light chain amyloidosis–associated myopathy and to provide guidelines for recognition. Patients and MethodsFifty-one patients with systemic immunoglobulin light chain amyloidosis and biopsy-confirmed muscle amyloid deposition diagnosed between January 1, 1995, and December 31, 2015, were included in this study. ResultsCommon presenting symptoms were muscle weakness in 49 patients (96%), dysphagia in 23 (45%), myalgia in 17 (33%), macroglossia in 17 (33%), jaw claudication in 13 (25%), and hoarseness in 9 (18%). The median time from the onset of symptoms to diagnosis was almost 2 years. Less than two-thirds of the patients with an outside muscle biopsy (16 of 27) had an established pathologic confirmation of amyloidosis due to failure to routinely incorporate Congo red staining. Moreover, 12 patients were incorrectly treated before diagnosis of amyloid myopathy. More than half of the patients had normal creatine kinase levels at diagnosis. Cardiac troponin T levels were elevated above the reference range in 5 of 12 patients who lacked evidence of cardiac involvement. Median overall survival was 32 months. Factors associated with inferior survival were involvement of more than 2 organs (median survival, 13 months), cardiac involvement (median survival, 15 months), and absence of stem cell transplant (median survival, 18 months). With the exclusion of patients treated with stem cell transplant, no improvement in survival was seen over the 1995-2004 and 2005-2015 decades. ConclusionImmunoglobulin light chain amyloidosis–associated myopathy is rare. Delay in diagnosis is common, and there is a high rate of pathologic and clinical misdiagnosis. Awareness of elevation of cardiac troponin T levels in the absence of cardiac disease may be a clue to diagnosis.

A rare gastrointestinal manifestation of systemic primary amyloidosis

Symptomatic gastrointestinal (GI) amyloidosis is a rare manifestation of systemic amyloid light chain amyloidosis. Further, the presentation of primary GI amyloidosis without previously diagnosed systemic amyloidosis is exceptionally rare. We describe a case of a patient presenting with abdominal pain, nausea, vomiting, and weight loss later to be diagnosed with localized GI amyloidosis from underlying multiple myeloma. Unfortunately, the GI disease was insurmountable leading to her death. Amyloidosis exerts its pathology at the level of the mucosa, soft tissue, nerves, and vascular supply of the GI tract. No specific treatments for the GI complications of amyloidosis are available and supportive measures are universally employed. GI amyloidosis is not only infrequently amenable to systemic and symptomatic treatment, but has a negative impact on both quality of life and survival.

58-year old patient with atypical peritoneal manifestation of diffuse amyloid deposition: presentation of systemic Amyloid Light-chain (AL) amyloidosis in B-mode imaging and contrast-enhanced ultrasound (CEUS)

58-year old patient with atypical peritoneal manifestation of diffuse amyloid deposition: presentation of systemic Amyloid Light-chain (AL) amyloidosis in B-mode imaging and contrast-enhanced ultrasound (CEUS)

Long-term event-free and overall survival after risk-adapted melphalan and SCT for systemic light chain amyloidosis

Stem cell transplantation (SCT), an effective therapy for amyloid light chain (AL) amyloidosis patients, is associated with low treatment-related mortality (TRM) with appropriate patient selection and risk-adapted dosing of melphalan (RA-SCT). Consolidation after SCT increases hematologic complete response (CR) rates and may improve overall survival (OS) for patients with <CR. We retrospectively analyzed outcomes for 143 patients who underwent RA-SCT with or without consolidation. Melphalan was administered at 100 (14%), 140 (52%) and 200 (34%) mg/m2. The TRM rate at 100 days was 5%. RA-SCT resulted in CR in 24% (3 months) and 48% (12 months) of patients. The CR rate was particularly high (62%) in patients offered bortezomib consolidation. With a median follow-up among survivors of 7.7 years, median event-free survival (EFS) with RA-SCT was 4.04 years (95% confidence interval (CI): 3.41–5.01 years); median OS was 10.4 years (95% CI: 7.3–not achieved). Patients with CR at 12 months after SCT had significantly longer EFS (P=0.01) and OS (P=0.04). In a multivariate analysis, melphalan dose had no impact on EFS (P=0.26) or OS (P=0.11). For selected patients, RA-SCT was safe and was associated with extended long-term survival. With the availability of novel agents for consolidation, RA-SCT remains a very effective and important backbone treatment for AL amyloidosis.

Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study

AbstractCytogenetic aberrations detected by interphase fluorescence in situ hybridization (iFISH) of plasma cells are routinely evaluated as prognostic markers in multiple myeloma. This long-term follow-up study aimed to assess the prognosis of systemic light chain amyloidosis (AL) patients treated with high-dose melphalan (HDM) chemotherapy and autologous stem cell transplantation, depending on iFISH results. Therefore, we analyzed a consecutive cohort of 123 AL patients recruited from 2003 to 2014. HDM was safe, with only 1 of 123 patients dying as a result of treatment-related mortality, and effective, with a complete remission (CR) rate of 34%. Translocation t(11;14) as the most prevalent aberration (59%) led to an improved CR rate after high-dose therapy (41.2% vs 20.0%; P = .02), translating into a prolonged hematologic event-free survival (hemEFS; median, 46.1 vs 28.1 months; P = .05) and a trend for better overall survival (median, not reached vs 93.7 months; P = .07). In multivariate analysis, t(11;14) was confirmed as a favorable prognostic factor regarding hemEFS along with lower values for the difference between involved and uninvolved free light chains. Conversely, deletion 13q14, gain of 1q21, and hyperdiploidy had no significant prognostic impact. The high-risk cytogenetic aberrations t(4;14), t(14;16), and del(17p13) conferred an unfavorable prognosis, although statistical significance was reached only for univariate CR analysis in this small group of 9 patients. Thus, t(11;14) positivity in HDM-treated AL patients conferred superior CR rates and hemEFS. In view of the reduced response of t(11;14) to bortezomib, this highlights the impact of therapy on the prognostic role of cytogenetic aberrations.

Breast amyloidosis: a case report

Amyloidosis is an uncommon disorder characterized by extracellular deposition of abnormal proteins. Breast involvement has rarely been reported and can clinically be misdiagnosed as breast cancer. A 60-year-old woman presented with a 3-mm diameter mass in the right breast close to a silicon implant positioned 20 years before. A core biopsy, performed to rule out breast cancer, showed amyloid deposit. Further exams confirmed a systemic amyloid light chain amyloidosis. After few months the mass increased causing breast volume and shape distortion. Since breast cancer may be the cause of amyloid deposits or be hidden by it, the patient underwent a bilateral skin sparing mastectomy and expander and fat grafting breast reconstruction. The resection specimens showed amyloid deposits only, no evidence of cancer. At 2 years follow-up, no breast amyloidosis recurrence was shown. Breast amyloidosis is rare but can occur in a plastic surgeon’s practice. It is mandatory to rule out a comitant breast cancer or systemic amyloidosis.

Flow cytometry-based characterization of underlying clonal B and plasma cells in patients with light chain amyloidosis.

Systemic amyloid light chain (AL) amyloidosis is a life‐threatening protein deposition disorder; however, effective therapy can dramatically improve the prognosis of AL patients. Therefore, accurate diagnosis of the underlying hematologic disease is important. Multi‐parameter flow cytometry (MFC) is a reliable method to analyze lymphatic neoplasias and to detect even a small lymphatic clone. We analyzed the presence of clonal plasma cell (PC) and B cells in the bone marrow of 63 patients with newly diagnosed AL amyloidosis by MFC. We compared the results with the levels of monoclonal protein, the histopathology and cytogenetic results. As reference of light chain restriction, we used the immunohistochemical results of κ or λ positive amyloid deposits in various tissues. MFC identified underlying clonal lymphatic cells in all but two patients (61 of 63, 97%). Sixty‐one patients harbored malignant PCs, whereas B‐cell lymphomas were identified in two patients. Furthermore, MFC indicated at least one putative immunotherapeutical target (CD20, CD38, CD52, or SLAMF7) on malignant PCs in all but one patient. These results demonstrate that MFC is a reliable tool for an accurate diagnosis of the underlying hematologic disease and the detection of potential immunotherapeutical targets in patients with AL amyloidosis.