ALBERT

Description: Abstract 5007 Introduction: Amyloidosis is characterized by extracellular deposition of abnormal insoluble fibrillar proteins. The two most frequent systemic amyloidoses are the light-chain (AL amyloidosis) and familial transthyretin (ATTR) forms. Clinical presentations often vary between the two types. Macroglossia is viewed as pathognomic of AL amyloidosis, and has not previously been described in patients with hereditary TTR amyloidosis. Here, we describe two cases of systemic amyloidosis with macroglossia in which immuno-electron microscopy diagnosed ATTR in one and AL in the other. Case Presentations: A 61 year old woman presented initially to her general internist with weight loss, difficulty swallowing, and tongue numbness. Her clinical exam revealed macroglossia and peripheral neuropathy. Tongue and axillary lymph node biopsies demonstrated amyloid deposits by Congo red staining. There was no evidence of renal, cardiac or other vital organ involvement. She had no evidence of a plasma cell dyscrasia with negative serum and urine immunofixation electrophoresis, normal serum free light chain concentration and ratio as well as polytypic plasma cells in the bone marrow. Immuno-electron microscopy using gold-labeled antibodies was performed on the tongue biopsy. The fibrils were immunoreactive with anti-TTR but not anti-kappa, anti-lambda, or anti-AA antibodies. DNA sequencing identified a known amyloidogenic T60A TTR mutation in exon 3 of chromosome 18, confirming the diagnosis of ATTR with amyloidotic polyneuropathy and macroglossia. The second case involved a 59 year old man with renal insufficiency. He complained of fatigue, weight loss, and tongue swelling. Physical examination was significant for macroglossia and submandibular gland enlargement. Tongue biopsy demonstrated amyloid deposits by Congo red staining. As in the previous case, markers of plasma cell dyscrasia with clonal plasma cells in the bone marrow, blood, and urine were absent. Immuno-electron microscopy of the tongue biopsy documented antibody reactivity to lambda light chain and not TTR, kappa light chain or AA proteins, confirming the diagnosis of AL amyloidosis. He subsequently underwent treatment with high dose intravenous melphalan followed by stem cell transplantation achieving a good clinical response sustained for 2 years to date. Discussion: While macroglossia is thought to be pathognomonic of AL amyloidosis, we report a case of macroglossia with fibrillar ATTR amyloid deposits diagnosed by immuno-electron microscopy. This is contrasted with a clinical presentation consistent with AL in which routine laboratory testing failed to identify evidence of a plasma cell dyscrasia. In both cases, electron microscopy demonstrated immunoreactivity for the fibrils of a single pathogenic protein. The first case was confirmed by DNA sequencing, and the second had a typical response to anti-plasma cell chemotherapy, in spite of the lack of identifiable markers of disease. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2394 Background: Treatment of AL amyloidosis with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT) results in hematologic complete response (CR) in 40% of patients and a median survival of about 5 years. Hematologic CR is associated with improved organ function and long survival. Whether patients who fail to achieve CR have any benefit from HDM/SCT has not been examined in a large series of patients. OBJECTIVE: The aim of this study was to investigate the outcome of patients with AL who do not achieve a CR after HDM/SCT and assess the transplant-related mortality (TRM) at a single specialized referral center. DESIGN and PATIENTS: Retrospective analysis of 421 patients with AL amyloidosis treated with HDM/SCT (100 to 200 mg/m2) in the Amyloid Treatment and Research Program at Boston Medical Center between July 1994 and December 2008. The subgroup of patients who did not achieve a CR at 1 year after transplant was analyzed in detail to assess their outcome in terms of organ response, event-free survival (EFS) and overall survival (OS). The median follow-up was 4 years (range, 0 to 15.6) for the entire cohort and 6.3 years (range, 1 to 15.6 years) for surviving patients. RESULTS: Three hundred and forty patients out of 421 included in the study (81%) were evaluable for response at 1 year post-HDM/SCT. The CR rate among the 1-year survivors was 43% while 195 patients (57%) did not achieve a CR, defined as disappearance of all signs of monoclonal gammopathy and bone marrow plasmacytosis. By consensus criteria, organ response rate in the non-CR group was 53.3%, compared to 78.6% for CR-patients (p

Description: Abstract 3553 Treatment of AL amyloidosis (AL) and monoclonal immunoglobulin deposition disease (MIDD) with high dose melphalan and autologous stem cell transplant (HDM/SCT) offers a high rate of durable complete hematologic responses and leads to clinical responses and improvement in survival. The development of end-stage renal disease (ESRD) is common among patients with AL amyloidosis and MIDD-associated renal disease leading to requirement for renal replacement therapy. Because of toxicity associated with HDM/SCT, there has been concern about its safety in patients with ESRD Therefore the role of HDM/SCT for patients with renal insufficiency has been called into question. Here we report on standard operating procedure, toxicities, hematologic responses and survival of patients with ESRD treated with HDM/SCT for AL amyloidosis and MIDD. Between 7/1994 and 6/2010, 32 patients with AL amyloidosis and 4 patients with MIDD associated ESRD were treated with HDM/SCT. The median age was 53 (range, 28–68). There were 21 (58%) males and 18 (50%) with kappa clonal plasma cell dyscrasia. Organ involvement distribution was typical for this disease: 75% patients (n=27) had 2 or more organs involved; 25% (n=9) had only renal involvement and 28% (n=10) had symptomatic cardiac involvement. The median duration of dialysis-dependence prior to HDM/SCT was 3.4 months and the median time from diagnosis to HDM/SCT was 6.5 months. Peripheral blood stem cells were mobilized using G-CSF alone at 10–16 m/kg/day for 3–4 days. Melphalan was administered intravenously in divided doses on 2 consecutive days. Oral cryotherapy was administered during and 15 minutes before and after infusion of melphalan since 2/2002 to reduce the incidence and severity of mucositis. The total dose of melphalan ranged from 100–200 mg/m2, depending on age, severity of cardiac disease and performance status. Stem cells were infused 24–72 hours after completion of melphalan. Hemodialysis patients were dialyzed according to the patient's usual schedule but with an interval of at least 2 hours between the administration of melphalan or infusion of stem cells and the initiation of hemodialysis. An extra session of hemodialysis was performed either on the second day of melphalan infusion and/or the day of stem cell infusion. Peritoneal dialysis exchanges were performed according to the patient's usual schedule. Antimicrobial prophylaxis with an oral quinolone, acyclovir and fluconazole was started on D + 1. Five patients received peritoneal dialysis and the remainder received hemodialysis. Thirty-one % (n=11) received 200 mg/m2 HDM, 47% (n=17) 140 mg/m2 HDM and 22% (n=8) 100 mg/m2 HDM. Treatment-related mortality, defined as deaths within 100 days of SCT, occurred in 6% (n=2/36). There were no deaths during stem cell mobilization and collection or stem cell infusion. There were additional 7 deaths (19%) during the first year after HDM/SCT. Hematologic response was assessed at 1 year following HDM/SCT. Hematologic complete response (CR) was defined as absence of monoclonal gammopathy by serum and urine by IFE, absence of clonal plasma cells in the bone marrow, and normalization of serum free light chain concentration and ratio since 2003. CR occurred in 70% (n=19) of 27 surviving patients at 1 year following HDM/SCT. The median time to neutrophil and platelet engraftment was 10 and 14 days, respectively. The median number of red cell and platelet transfusion was 4 units and 6 packs, respectively. Thirteen (36%) patients developed grade 3 or 4 mucositis. Of note, 45% (n=10/22) developed grade 3 or 4 mucositis before institution of oral cryotherapy compared to 14% (n=2/14) after its initiation (p=0.07). The median survival for the entire group of 36 patients is 64 months (5.3 years) from the time of SCT. The median survival is 62 months from the time of initiation of dialysis. The median survival is 74 months (6.1 years) for the patients achieving a CR compared to 38 months (3.1 years) for those not achieving a CR (p=0.439). Nine patients with hematologic CR have either undergone or are awaiting renal transplantation. In conclusion, HDM/SCT is an effective treatment in selected patients with AL amyloidosis or MIDD associated ESRD with treatment-related morbidity and mortality and outcomes similar to those for non-dialysis patients. Disclosures: No relevant conflicts of interest to declare.

Description: Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR.

Description: Abstract 4084 AL amyloidosis is a plasma cell dyscrasia in which clonal immunoglobulin light chains misfold, forming fibrils that are deposited in tissues and vital organs. Immunomodulatory drugs including thalidomide, lenalidomide (LEN), and pomalidomide have activity in AL amyloidosis. We conducted a prospective phase II trial of LEN with dexamethasone (DEX) in the treatment of AL amyloidosis (ClinicalTrials.gov: NCT00091260), enrolling 82 patients from 2004–2011. We now report the final results of this trial. The majority of the patients were treated with LEN at a starting dose of 15 mg/d for 21 days out of a 28 day cycle, and received DEX at 20 or 40 mg weekly, depending upon age, congestive heart failure, and/or peripheral edema, and aspirin prophylaxis for venous thromboembolism (VTE) was used for most. Of the 82 patients, the median age was 62 (range, 40–84) and 63% were men. 95% of the patients had prior therapy for AL, often including high dose melphalan and autologous stem cell transplantation. The median number of cycles delivered was 11 (range, 1–69). Of the 68 evaluable patients, 16% achieved a complete hematologic response, 44% achieved a partial hematologic response, 9% achieved a minor hematologic response, and 29% had no response to treatment. The median time to best hematologic response was 6 months. Sixty-three patients had quantifiable organ involvement prior to treatment with LEN/DEX, and 44% of those patients had measurable organ response. Reasons for discontinuation of study drug were side effects (29%), non-response (39%) and complete response or completion of trial (15%). The most common side effects during treatment were fatigue (88%), anemia (67%), muscle cramps (66%), dizziness/lightheadedness (60%), respiratory tract infections (55%), increased creatinine (56%) and skin rash (48%). In conclusion, LEN administration achieved a 60% hematologic response rate (CR+PR) even in heavily pre-treated AL patients, when used at a starting dose of 15 mg/d with weekly dose-modified DEX, VTE prophylaxis, and appropriate management of side effects. Disclosures: Off Label Use: Lenalidomide for AL amyloidosis. Sanchorawala:Millennium: Research Funding. Zeldis:Celgene: Employment. Seldin:Celgene: Research Funding.