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Abstract 4074 AL amyloidosis is caused deposition of monoclonal immunoglobulin light chain and is associated with IgM-paraproteinemia in 5% of cases – mostly due to underlying Waldenstrom's macroglobulinaemia. The standard treatments for AL amyloidosis are typically regimes derived from multiple myeloma and are inappropriate in this group of patients. Response to alkylating agents is poor and there is no agreed standard treatment. We describe here the treatment and outcome of 297 patients with IgM-related AL amyloidosis, with particular focus on the impact of outcomes when treated with regimes developed specifically for Waldenstrom's macroglobulinaemia. 267 consecutive IgM patients with AL amyloidosis were identified form the databases of amyloidosis groups based in London, UK, Pavia, Italy and Limonges/Tolouse/Paris, France- evaluated between 1988 and 2011. 64% of patients had underlying lymphoma mainly of lymphoplasmocytic subtype; lymph node amyloid was present in 18%. Commonest organ involved was the kidney (64%) followed by heart (42%). Serum free light chain ratio was abnormal in 163 (72%) patients with baseline difference between uninvolved and uninvolved FLC (dFLC) >50 mg/L in 124 (54%) cases. 135 patients required therapy, of whom 124 were evaluable for frontline regimen: chlorambucil/melphalan in 57, rituximab-containing regime 60 (23%) (R-CVP, FCR, RCD, R-Bortz, R-CHOP, others), purine analogs in 44 (17%), bortezomib containing 24 (8%), R-CHOP and R-CD in 18 (7%) and 20 (8%). 9 (3%) had high dose melphalan followed by autograft. The haematological response rate on an intention to treat basis was 28% (41% for evaluable patients) with only 2% VGPR or better. Median time to next treatment was 10 months with a better outcome for frontline HDM, CHOP/CVP and FCR (median 49, 16 and 13mo, respectively) with 50% responders. Median OS was 48 months. Presenting dFLC >180mg/L was predictive of poorer outcomes - median survival 48 months for patients with dFLC 180mg/L. The Mayo cardiac stage at presentation was strongly predictive of outcomes with median survival of stage 1 – 74 months, stage 2 24 months and stage 3 – 10 months. Although complete response rates were low, there was a significant survival advantage for patients achieving at least a partial response with estimated 3 year survival of 78% for responders vs. 55% for non-responders (figure 1).: There was a survival advantage for patients receiving HDMel, bortezomib combination (median OS not reached) and FCR (78mo) compared to (R)CHOP/CVP or FC regimens (median OS 42 and 31mo). In summary, the overall treatment responses in patients with IgM associated AL amyloidosis are poor. Presenting free light chains and cardiac biomarkers are prognostic factors in patients with IgM associated AL amyloidosis. Patients with IgM related AL amyloidosis should be treated with appropriately tailored regimens for the underlying lymphoproliferative disorder to achieve at least PR. Exposure at some stage to bortezomib, FCR or HDM appears to be associated with better survival. Figure 1: Overall survival stratified by degree of haematological response Figure 1:. Overall survival stratified by degree of haematological response Disclosures: Roussel: janssen: Honoraria; celgene: Honoraria. Wechalekar:Janssen-Cilag: Honoraria.

Abstract 2966 Introduction: Poor survival in AL amyloidosis is largely driven by outcomes in patients with advanced cardiac disease. To date, the Mayo cardiac staging system is the most widely used tool to identify these high risk patients. For stage III patients few treatment options exist to modify the natural history of this disease with up to 50% dying within the first 6 months. Moreover, there are currently no studies comparing different regimens in the novel agent era specifically addressing this group. Here we present a matched comparison examining response and survival endpoints after upfront treatment in Mayo stage III patients using either Cyclophosphamide, Bortezomib and Dexamethasone (CVD) or Cyclophosphamide, Thalidomide and Dexamethasone (CTD), the current standard of care for this disease in the United Kingdom. Patients and Methods: The primary cohort comprises 78 patients (39 in each arm) referred to the National Amyloidosis Centre in London between 2008–2012. All patients had cardiac involvement by the 2005 consensus criteria and all were Mayo stage III. The CVD cohort reflects all patients seen at the NAC with Mayo stage III disease treated with this regimen upfront. Based on baseline NT-proBNP (>8000ng/L) and dFLC (>180mg/L) the patients were then matched with a recent cohort treated with CTD as first line therapy. The CVD and CTD regimens were recommended as previously described (1, 2). Dose modifications were at the discretion of the treating haematologist. Both conventional haematologic responses and dFLC responses were examined (3, 4). Overall survival (OS) was calculated by the Kaplan-Meier method and calculated from the start of treatment until death or last follow-up. To correct for the influence of early deaths on response rates a landmark analysis was performed in patients surviving at least 3 months from treatment (n=21 (CVD) and n=30 (CTD)). Results: In the intention-to-treat (ITT) cohort response rates are comparable although there was a trend to higher CR rates with the CVD regimen (table 1). On an ITT basis, there was no statistically significant difference in the 1-year OS (59.4% vs 46.2% for CVD and CTD respectively, p = 0.9, figure 1a). A high rate of early deaths is noted. 23.7% of CVD and 13.1% of CTD patients died within 6 weeks (p = 0.24). 36.8% of CVD and 23.7% of CTD patients died within 3 months (p = 0.22). In the landmark analysis upfront therapy with CVD correlated with an improved 1-year OS (94% vs 62.1%, p = 0.01, figure 1 b). This may be partly driven by the increased CR rate in the CVD cohort compared to those receiving CTD (47% vs 24% respectively, p = 0.03, table 1). Conclusion: Compared with CTD, treatment with CVD was not associated with a reduction in the high rate of early deaths often seen in patients with Mayo cardiac stage III disease. However, these data suggest that survival of patients treated with CVD upfront may be superior among those who remain alive after the first 3 months, consistent with the higher CR rates achieved. While it did not reach statistical significance the high rate of early deaths indicates that further optimisation and better supportive care strategies are required during the early stages of treatment especially with CVD. Ongoing phase III trials are currently underway to address these issues in a prospective manner. The ITT cohort is shown in (A) and the landmark cohort is shown in (B). Solid and dashed lines reflect CVD and CTD treated patients respectively. Disclosures: Wechalekar: Janssen-Cilag: Honoraria.

Introduction Cardiac involvement drives prognosis in Systemic AL Amyloidosis, predicting outcome and influencing therapeutic options. Current methods of cardiac assessment do not quantify the myocardial amyloid burden. We used Equilibrium Contrast Cardiovascular Magnetic Resonance (EQ-CMR) to measure the cardiac interstitial compartment, measured as the myocardial contrast volume of distribution, Vd m , which we hypothesised would reflect the amyloid burden. Methods Patients with systemic AL amyloidosis undergoing routine work up at the National Amyloidosis Centre were recruited (n=60, 39 males, 21 females, mean age 63 years) and underwent conventional CMR including late enhancement, EQ-CMR to measure Vd m and standard cardiac work-up including ECG, echocardiography, biomarkers (BNP, Troponin T) and functional assessment (6-min walk test, 6MWT, where permitted by autonomic neuropathy). Results were compared to normal controls. Conventional assessment ranked cardiac involvement as definite, probable and none. Results Vd m was significantly higher in patients than normal controls (0.25 vs 0.40, p m of 0.276 vs 0.342 vs 0.488, p m correlated with cardiac parameters by echo (eg, TDI S-wave R 2 0.27, p 2 0.31, p 2 0.47, p 2 0.28, p=0.006). Vd m was associated with ECG abnormalities and tracked small QRS voltages (R 2 0.33, p m correlated with a lower 6MWT outcome (R 2 0.13, p=0.03). Conclusions The measurement of the myocardial interstitial compartment (Vd m ) using EQ-CMR in systemic AL amyloidosis quantifies the cardiac amyloid burden.

Background Cardiac MRI (CMR) is increasingly used to further investigate patients in whom amyloidosis is suspected on echocardiography. Late gadolinium enhancement (LGE) reflects expansion of the interstitium, and circumferential subendocardial LGE has been reported to be a typical finding in AL amyloidosis; by contrast, a more diffuse transmural LGE pattern has been associated with ATTR (transthyretin amyloidosis).

Abstract 3975 Background: Elderly patients with AL amyloidosis present a unique therapeutic challenge. Both the disease itself and other co-morbidities contribute to organ dysfunction, potentially limiting treatment options. Despite this, durable responses can be achieved leading to both improvements in quality and longevity of life. Here we present our experience with patients > 75 years (yrs) enrolled in the UK-wide ALchemy study. Patients and Methods: ALchemy was designed to collect comprehensive treatment, outcome and toxicity data in newly diagnosed patients attending the National Amyloidosis Centre in the UK. Analysis of prospectively collected data revealed 46 pts > 75 yrs who were enrolled in the study beginning in 2009. 8 patients still alive at last assessment but having < 3m follow-up were excluded. Haematologic response was 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 between 50–90% defined a partial response (PR) and a dFLC of >90% defined a very good partial response (VGPR). The analysis was performed on an intention-to-treat basis and patients who died prior to response assessment were defined as non-responders. Overall survival (OS) was calculated by the Kaplan-Meier method and calculated from diagnosis until death or last follow-up. Results: The final cohort comprised 38 patients. Median age was 78.0 years. Median follow-up was 8.7 months (m). 37 patients had complete information for Mayo staging and 37% were stage III. 3 patients did not receive therapy. 20 patients received CTD as first line therapy, 4 received Mel/Dex, 4 received MPT, 1 received CVD, 3 received CD, 1 received RCD and 2 received CVP-R given baseline IgM secreting clonal B-cell lymphoproliferative disorders. 46% received less than 4 cycles of the planned upfront therapy. Overall response rate (RR) was 68% (11% attained a CR). 65% attained a partial dFLC response and 22% attained a VGPR. 9 patients received second line therapy. 5 were treated for relapsed disease, none of whom bettered their previous haematologic response but 2 patients attained a VGPR. Of the 4 patients who were treated for sub-optimal response none bettered their previous response. A correlation between receiving at least 3 cycles of therapy and attaining a CR or VGPR was observed (correlation coefficient 0.23, P = 0.09 and 0.42, P = 0.009 respectively). Median OS for the entire cohort was 10.7m. 45% died within one year of diagnosis. Median OS for Mayo stage III patients was 6.2 months. Attaining a VGPR by dFLC criteria correlated with a statistically significant improvement in OS compared with patients who did not achieve this milestone (median not reached vs 9.8m respectively; P = 0.016). A similar trend in OS was seen in patients who attained a CR but this did not reach statistical significance (median not reached vs 9.8m respectively; P = 0.192). Discussion: Treatment of elderly patients with AL amyloidosis remains a challenge. From our analysis despite receiving standard of care, median OS is < 1 year. However, based on this study appropriate treatment resulted in both attainment of CRs and VGPRs. Both endpoints are important treatment milestones previously shown to correlate with improved survival, and this is further corroborated here. Median OS was not reached in patients achieving either a CR or VGPR. Unfortunately, CR and VGPR rates remain < 25% in this population and it appeared that at least one factor is the inability to complete 3 cycles of treatment. Further study examining this distinct group of patients is warranted with the aim to develop therapeutic regimens balancing both effectiveness and tolerability. Disclosures: No relevant conflicts of interest to declare.

Abstract 992 Background: There have been few prospective clinical trials in AL amyloidosis; existing prospective studies in this heterogeneous disease have been hampered by small patient numbers due to rarity of the condition, a lack of validated endpoints and high cost. More importantly, they have been subject to considerable bias due to almost complete exclusion of poor prognosis patients. Aims: The aims of this prospective observational study, was to include all patients with systemic AL amyloidosis regardless of age or disease severity, in order to convey a ‘real-world' picture of the disease, its response to myeloma-type chemotherapy regimens, associated toxicity and outcomes in terms of amyloidotic organ function, quality of life (QoL) and survival. Methods: All patients referred to the UK National Amyloidosis Centre (NAC) from 1st September 2009 were screened for participation in the AL chemotherapy study (ALchemy). Patients were eligible if they were newly diagnosed with systemic AL amyloidosis and in need of chemotherapy. At each NAC evaluation (baseline, after completion of 3 cycles of chemotherapy and 6, 12, 18 and 24 months) the underlying clonal disease was assessed by sFLC assay and serum and urine electrophoresis; amyloidotic organ dysfunction/response was assessed according to the international consensus criteria. At baseline patients underwent bone marrow examination, assessment of whole-body amyloid load by 123I-SAP scintigraphy, and completed a QoL questionnaire. Amyloid burden was monitored 6 monthly thereafter, and QoL after 3 cycles and yearly thereafter. Clonal disease assessments were undertaken monthly throughout the duration of the study and toxicity assessments during periods of chemotherapy. Patients received chemotherapy in local hematology centers and regimens and doses were at the discretion of treating physicians. Results: Two hundred and fifty patients were recruited in 2 years; 57% were male. Median age at presentation was 64 years (IQR 57 to 73). At baseline evaluation, which occurred a median of 1 month from diagnosis, 20% of patients had Mayo stage 1 disease, and 40% each had stage 2 and 3 disease. Renal (50%) and cardiac (31%) presentations predominated. At censor, 9 (4%) patients had died prior to starting chemotherapy and 217 (87%) patients had received at least one cycle and were thus considered ‘evaluable'. First-line treatment was with CTD in 168 (77%) cases, 89% of whom received dose attenuation. Nineteen (9%) patients received a melphalan- or bortezomib-based regimen first line. One third of those patients who commenced chemotherapy underwent a regimen change, usually (82%) to one containing bortezomib, either as monotherapy (9 patients) or in combination with dexamethasone and/or cyclophosphamide (47 patients). On an intention to treat basis, 20% patients died before reaching the 3 cycle timepoint and a further 9% were withdrawn or lost to follow up. Among the 154 remaining evaluable patients, the 3 cycle evaluation resulted in continuation of the same chemotherapy regimen in 42% cases, a switch of regimen in 21% cases, and cessation of chemotherapy altogether in 28% cases. At this timepoint, clonal CR, VGPR, PR and NR rates among evaluable patients were 35%, 9%, 30% and 26% respectively. Toxicity ≥grade 3 occurred in 49% of patients with a total of 359 episodes. The commonest severe toxicities were fluid overload (61%), lethargy (38%), infection (26%), hypotension (18%) and neuropathy (12%). Of 217 patients, 111 (51%) were admitted with a total of 148 hospitalizations, most commonly due to fluid overload or infection. After median follow-up of 7 months, 29% of patients had died. Mayo stage 3 disease, dominant cardiac presentation and inadequate clonal response after 3 cycles were independent risk factors for death. Achieving a dFLC response >65% after the first cycle of chemotherapy, appeared to overcome the poor prognosis associated with Mayo Stage 3 disease. Conclusion: ALchemy is fast becoming the largest prospective study in AL amyloidosis and has provided a wealth of information on treatment, toxicity and outcome in a real-world clinical setting. The inclusion of most patients, regardless of disease severity, indicates a persistently poor prognosis among a substantial proportion of patients who are ineligible for randomized controlled trials, and highlights the unmet need for improved diagnosis and treatment. Disclosures: No relevant conflicts of interest to declare.

Abstract 988 The treatment of patients with systemic AL amyloidosis remains challenging. Cyclical combination chemotherapy is used in majority of patients but a report that I.V. melphalan-dexamethasone may not overcome the poor prognosis for cardiac amyloidosis (Deitrich S et al, Blood, 116, 2010) has fuelled the controversy about best front line treatment. We report outcomes of 428 patients treated with oral cyclophosphamide thalidomide dexamethasone (CTD), oral melphalan dexamethasone (M-dex), bortezomib dexamethasone with or without an alkylator (BD), cyclophosphamide-lenalidomide-dexamethasone (CLD) or stem cell transplant (ASCT) as first line treatment for systemic AL amyloidosis assessed at three large European amyloid centres in London (UK), Pavia (Italy) and Athens (Greece) between 2003–2010. Patients with a full baseline data set were included in the study. Clonal and organ responses were defined according to the international amyloidosis consensus statement (Gertz et al 2005) and responses were assessed at 6 months or at the end of treatment. dFLC (difference between involved and uninvolved free light chain (FLC)) was used to assess the absolute FLC change after treatment. 204 (48%) received M-dex, 155 (36%) received CTD, 13 (3%) received ASCT, 28 (7%) received BD and 25 (6%) received CLD. The median number of cycles received was 5 for all regimens. 257 (60%) had cardiac involvement, 325 (76%) had renal and 59 (14%) had liver involvement. Cardiac involvement by regime was: BD 75%, CLD 68%, M-dex 65%, CTD 45% and ASCT 23%. 30 (7%) died within six months of diagnosis. The median number of organ involved was 2 (range 1–5) with ECOG performance status ≥2 in 123 (28%). 98 (23%) patients achieved a complete response (CR), 175 (41%) achieved a partial response (PR) and 125 (29%) did not respond to treatment. A haematological CR/PR was seen, respectively, in 22%/41% treated with CTD, 26%/44% with M-dex, 23%/46% with ASCT, 39%/42% with BD and 4%/44% with CLD. There was significantly greater reduction in dFLC after BD (median reduction 91% over starting value) compared to CTD (median 81%; p = 0.006), M-Dex (median 83%; p = 0.004) and CLD (median 72%; p = 0.03). There was no significant difference in the median dFLC reduction between patients treated with CTD and M-Dex. 100/325 (30%) had a renal organ response, 17/59 (29%) had a hepatic response and 24/257 (9%) had a cardiac response, and 61 (16%) had a cardiac response by NT-proBNP criteria. The organ and NT-proBNP responses respectively were highest in the cohort treated with BD (53% and 32%) followed by CTD (38% and 12%), ASCT (30%), M-dex (23% and 19%) and CLD (12% and nil). CTD achieved significantly better organ responses compared to M-dex (p=0.0024). At median follow up of 29 months, median overall survival (OS) for the whole cohort has not been reached with 2, 3 and 4 year estimated survival of 75%, 65% and 61%, respectively. When patients with cardiac involvement were considered, those achieving a CR have not reached median OS with an estimated 3 year survival of 89%, those with PR had an estimated median OS of 50 months and the non-responders had a median OS of 21 months. Detailed comparison by Mayo stage will be presented. There was no significant difference in the OS of patients treated with CTD or M-Dex (as compared directly or by centre). In summary, outcome of patients with AL amyloidosis across three major European centres appears comparable. BD treatment achieves significantly lower end of treatment dFLC values compared to CTD, M-dex, ASCT or CLD – which importantly translates into an organ response in over half of all patients receiving BD compared to a third of those treated with CTD and quarter of those with M-dex and further follow up may yet reveal survival differences. Organ responses appear significantly better with CTD compared to M-dex – possibly due to more rapid response to CTD since the end of treatment dFLC values are not significantly different - although this does not translate into a survival advantage. Depth of clonal response appears to be directly linked to improvement in survival of patients with cardiac amyloidosis (including in patients treated with CTD and M-dex) and organ response in general. This study supports the rational for doing urgent phase III studies confirming benefits of bortezomib combination chemotherapy for upfront treatment in AL amyloidosis and the benefit of rapid deep clonal responses in cardiac amyloidosis irrespective of the regimen. Disclosures: Off Label Use: Thalidomide, bortezomib, lenalidomide. Dimopoulos:Celgene: Honoraria; Othro Boitech: Honoraria.

Abstract 2658 Introduction: Six minute walk distance (6MWD), is a measure of exercise capacity commonly used as an endpoint in pulmonary hypertension (PH) clinical trials. Many patients with sickle cell disease (SCD) have acute pain crises or chronic pain syndromes that impair their quality of life. While patients with SCD who are undergoing screening for PH are generally screened in steady state, i.e., when they have not had a recent pain crisis, the impact of chronic pain on exercise capacity in this group of patients has not been previously evaluated. Methods: walk-PHaSST was a multi-center screening study designed to identify subjects with SCD at increased risk for symptomatic PH, defined by a tricuspid regurgitant velocity (TRV) ≥ 2.7 m/sec and 6MWD between 150–500 meters, for enrollment in a double-blind placebo controlled trial of sildenafil. The primary endpoint was the change in 6MWD after 16 weeks of treatment. We examined the relationship between subjects' self-reported acute and chronic pain and baseline 6MWD in the screened SCD patients in walk-PHaSST. Results: For 90% of subjects, the information about pain was reported by the patient or parent/family member. Documentation of pain management and utilization of services was verified from medical records in 10% of subjects. Ninety four percent of all subjects reported having a history of acute sickle cell pain crises; 6% reported never having had an acute pain crisis. For the subjects who reported a history of acute pain crises, the ‘typical’ acute pain rating on a scale of 0 to 10 was ≥ 7 (maximum 10) for 77% of this subset of subjects. A total of 342 (50%) subjects reported not having had any pain crises in the preceding week. Of 720 subjects screened medical history and 6 MWD was available in 673 patients. Of these 633 (94%) subjects did not report having had a pain crisis requiring an emergency department visit or hospitalization in the preceding week. A total of 39% of subjects reported chronic sickle cell related pain; no rating was reported for chronic pain. 88% of patients reported using medications for pain control while 15% reported using non-drug therapy including physical therapy in 3%, alternative therapy in 2%, acupuncture in 2% and hypnosis in < 1% of patients. The mean 6MWD for the screened population was 439 meters (median 438 m, range 123–713 m). A total of 171/673 (26%) subjects had a 6MWD >500 meters, which was above the screening cut-off for enrollment in the main interventional trial. By univariate analysis, subjects reporting chronic pain had a significant lower odds ratio for walking > 500 meters (OR 0.637, 95% C.I 0.44–0.99); a similar observation was seen with those subjects with a history of acute pain crises (OR 0.47, 95% C.I 0.24–0.91). Multivariable logistic regression analysis revealed a significant inverse relationship between chronic pain but not acute pain and 6MWD after adjusting for age, TRV, gender, hematocrit and smoking history (See Table 1). The mean 6MWD decreased by 27 meters with self reported chronic pain after adjusting for TRV, age, gender, hematocrit and 6MWD. Conclusions: TRV is a known predictor of 6MWD. However, these data suggest that patient self reported sickle cell related chronic pain is also an independent predictor of 6MWD. This relationship raises interesting questions about the potentially confounding effects of pain on exercise capacity as assessed by the 6MW test. Further study is warranted to investigate an association between chronic pain and exercise capacity in SCD as well as exploration of appropriate endpoints for future clinical trials in patients with SCD and suspected symptomatic PH. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Rosenzweig:Pfizer: Research Funding. Badesch:Pfizer: Honoraria, Research Funding. Hassell:Novartis: Research Funding.

A previously well 69-year-old British man presented with a 4-week history of anorexia, weight loss, drenching night sweats, marked lethargy and abdominal pain. Examination revealed pleural effusions and gross ascites. There was no jaundice, fever, cough, signs of chronic liver disease or palpable lymphadenopathy. Investigations revealed a haemoglobin 12.9 g/dl, white cell count 11.3×109/litre, neutrophils 10.4×109/litre, platelets 704×109/litre; creatinine of 107 μmol/l; normal liver enzymes; corrected calcium of 2.23 mmol/l; lactate dehydrogenase 4640 U/l (normal 125–243 U/l); urate 1201 μmol/l (normal

Abstract 2869 Poster Board II-845 Introduction: Risk adapted CTD, oral MD and high dose melphalan with autologous stem cell transplantation (SCT) (in selected cases) have emerged as important frontline treatments in AL amyloidosis. We report the interim results of a randomised prospective pilot study designed to estimate response rates and test feasibility of two randomisations using these treatments for patients with newly-diagnosed systemic AL amyloidosis. The final analysis is due in October 2009 and final full study results will be presented at the meeting. Patients and methods: The trial recruited for 14 months from January 2008 in the UK. Twenty four patients each were planned to enter a high intensity (SCT versus CTD) or a low intensity randomization (MD versus CTD) respectively, depending on suitability for SCT. Eligibility for the high-intensity arm was deliberately stringent in order to minimize risk of transplant-related mortality. Primary endpoints were haematologic response by free light chain assay (measured at each cycle with landmark assessments at 3 and 7 months), safety and recruitment rate. A myeloma quality of life (QOL) questionnaire was piloted in the absence of a disease-specific questionnaire for AL amyloidosis at baseline and 7 months post randomisation. Results: The high intensity arm was closed early due to lack of recruitment, mostly from clinical ineligibility and no further results from this arm are reported. The low intensity arm successfully recruited the required 24 patients (12 in each group). Median (range) age at randomization was 66 (42-85) years and stratification was by ECOG performance status which ranged from 0 to 3 (21%, 33%, 33% and 13% of patients respectively). 24 (100%) and 16 (67%) patients have response assessments (or are not evaluable) at 3 months and 7 months respectively at the time of submission. One patient in each arm died and one patient in the MD arm withdrew prior to the 3 month assessment. Overall haematological response rate at 3 months (at least a PR) was similar between the two arms; 9 (75.0% (95% Confidence Interval 43% to 95%)) in the CTD arm versus 8 (66.7% (95% CI 35% to 90%)) in the MD arm. At 3 months, CR was achieved in 7 (58.3% (95% CI 28% to 85%)) CTD and 3 (25.0% (95% CI 6% to 57%)) MD patients. Final response data at 7 months will be presented at the meeting. Median (range) time to achieve at least a PR from commencement of chemotherapy was 88 (34-218) and 95 (74-133) days in the CTD and MD groups respectively. To date, 17 of the 24 patients have reached their maximal clonal response (10 CTD, 7 MD patients), two patients died before achieving maximal response and one patient is not evaluable as they withdrew prior to the first response assessment. 4 patients could still achieve maximal response once 7 month follow up is completed. Of those currently evaluable for a maximal response, 8 (80%) CTD patients had CR versus 3 (43%) MD patients and 1 (1%) CTD patient had PR compared with 4 (57%) MD patients. There were no treatment-related deaths in either arm. Seventeen of 24 (71%) patients experienced grade ≥ 3 toxicities during chemotherapy (10 CTD patients (83%) versus 7 MD patients (58%)) though only 9 were classified as trial medication related SAEs (serious adverse events) which appeared to be similar in each arm - 5 CTD versus 4 MD. Lethargy (n=6), worsening congestive heart failure/fluid overload (n=5), infections (n=7) and pain (n=4) were the most common grade 3/4 toxicities, again with no noticeable differences between the treatment groups. The EORTC QLQ-MY20 myeloma QOL questionnaire appeared valid for use in AL amyloidosis patients and showed comparable QOL among both groups. Conclusions: Randomisation to SCT versus combination chemotherapy is not feasible using the current criteria in the UK. These interim results suggest that CTD may compare favourably with MD with possible higher early CR rates with CTD. There is a general perception that CTD has greater toxicity than MD but in this study there was no evidence of increased SAEs in either group and the QOL was comparable. Further comparison of CTD and MD is warranted in a large phase III randomized trial, but in order to be feasible would require international collaboration. Disclosures: Off Label Use: Off label use of thalidomide.

Abstract 2814 Poster Board II-790 N-terminal fragment of brain natriuretic peptide is a cardiac biomarker that has prognostic significance in amyloidosis and NT-ProBNP can rapidly change after completion of chemotherapy. We and others who have previously reported such changes in NT-ProBNP to be of prognostic significance but there was no cardiac “progression” or “improvement” according to the international amyloidosis consensus criteria (Gertz et al 2005) in the majority - making this finding difficult to explain. We now report subtle changes in left ventricular systolic function using lateral wall tissue Doppler as a new robust and reproducible parameter correlating well with such changes in NT-ProBNP. Patients with cardiac amyloidosis as defined by the international consensus criteria who had good renal function (creatinine clearance >30ml/min), received chemotherapy and had a significant change in NT-ProBNP after chemotherapy were identified from the database of the UK National Amyloidosis Centre. A significant change in NT-ProBNP was defined as minimum rise or fall of 30% over the baseline pre-treatment value. Ninty seven patients with identified. All analysis was repeated on stored off line data on EchoPAC” in accordance with British Society of Echocardiography guidelines with special focus on ejection fraction (EF) (Biplane Simpson's method), longitudinal 2D strain, lateral TDI S wave (Tissue Doppler Imaging) and mean left ventricular wall thickness. At baseline the mean EF was 59%, mean LV wall thickness 13mm and mean TDI S wave velocity 0.07m/sec. 76/97 (78%) patients showed a significant increase in the NT-proBNP levels and 21/97 (22%) showed a significant a decrease. There was a significant correlation between the free light chain (FLC) level and NT-ProBNP at diagnosis (correlation coefficient 0.322; p NT-ProBNP changes after chemotherapy have remained difficult to explain. The international consensus criteria for cardiac progression or improvement by echocardiography - a 2 mm change in the LV wall thickness or 20% change in EF - are relatively insensitive and the clinical criteria (change in NYHA class by 2) are not robust or reproducible to detect cardiac improvement or progression. Lateral TDI S wave is a robust and reproducible parameter that correlates well with both an increase and decrease drop in NT-ProBNP levels. This suggests that there are subtle changes to the left ventricular systolic function which correlate well with change in NT-ProBNP and are of prognostic significance. These changes in systolic function occur well before any substantial diastolic functional change or change in wall thickness. This interesting finding needs further validation in larger groups and if confirmed should be considered for incorporation in the consensus criteria for cardiac progression or improvement. Disclosures: No relevant conflicts of interest to declare.

Abstract 2796 Poster Board II-772 Background: Risk stratification for patients with AL amyloidosis remains difficult. The Mayo staging system (Dispenzieri et al JCO 2004), based on cardiac biomarkers, is a widely accepted staging method. The Mayo staging cohort was diagnosed over a 21 year period during which the treatment for AL amyloidosis has completely changed. It also does not take into account the underlying clonal disease biology which is emerging as an independent prognostic factor. We propose a new staging for AL amyloidosis incorporating serum free light chains into the Mayo staging system using a much more uniformly treated cohort of patients. Methods: 212 patients with systemic AL amyloidosis attending the UK National Amyloidosis Centre between Jan 2001 and March 2008 with complete data sets (or stored sampled for retrospective testing) for FLC, NT-ProBNP and cardiac Troponin-T prior to any treatment were identified from the database. Patients with overt symptomatic myeloma were excluded from the analysis. Results: Median age was 64 years (range 26-88), male: female ratio was 1.3:1. Median serum creatinine was 149 μmol/L (37-1079), and 24 hour proteinuria 3.9g ( The cut-off for NT-ProBNP and troponin-T were based on the Mayo staging system (35 pMol/L and 0.03 ng/ml respectively) and iFLC cut-off was selected as 500 mg/L. The median overall survival for patients with values above and below the cut-off were: troponin-T – 0.4 yrs vs. 4.7 yrs (p500mg/L; those with abnormal NT-ProBNP – median OS was 4.6 yrs vs. 1.2 yrs (p=0.015) respectively for low and high FLC. iFLC >500 mg/L independently predicted for poorer OS in a multivariate model (p =0.016). A new staging system is proposed incorporating iFLC using the above mentioned cut-off values for NT-ProBNP, troponin-T and iFLC: Stage I - normal NT-ProBNP/troponin-T with low iFLC (median OS not reached); Stage II - high NT-ProBNP and low iFLC (median OS 4.6 yrs); Stage III - high iFLC (median OS 2 yrs); and Stage IV - abnormal troponin (median OS 0.4 yrs). At 18 months from diagnosis, 8% of stage I, 25% of stage II, 45% of stage III and 76% of stage IV patients had died. Stage IV patients were more likely to have not completed a full course of treatment (42%) compared to other groups (23% stage, 18% and 24% for the other three stages). 6% and 7% of stage I and II patients underwent an autologous stem cell transplant compared to none in the other stages. Conclusion: This new staging system for AL amyloidosis brings clonal markers in the stratification process. Patients with high troponin-T at presentation have a dismal outcome even with recent treatment advances which is unaffected by clonal parameters and need novel rapidly effective approach to treatment. In the other groups, the free light chains at presentation – a surrogate for the clonal burden – are prognostically important. This system offers better stratification of patients over the current system – it upstaged 14% Mayo stage I and 32% stage II patients. Adding the clonal markers may make this useful for addressing new questions in clinical trials. Given the low clonal burden in the good risk stage I patients, is the highest intensity treatment (i.e. ASCT) really needed and could they conceivably achieve the same outcome with less toxic short course treatment? This new staging system needs to be validated in independent patient groups and if validated should be adopted as a new amyloidosis staging system. Disclosures: Bradwell: The Binding Site: Equity Ownership.

Abstract 1791 Poster Board I-817 N-terminal fragment of brain natriuretic peptide (NT Pro-BNP) is a cardiac biomarker that is used as a prognostic marker at diagnosis in AL amyloidosis and has been reported to change serially following treatment, in line with clonal responses. With our Italian colleagues, we recently reported that changes in NT Pro-BNP post chemotherapy have marked prognostic significance – patients who do not achieve a 30% decrease having worse outcomes. We now report a transient post chemotherapy rise in NT Pro-BNP as a new phenomenon and assess its significance, relating it to renal and cardiac function and to assess whether this phenomenon impacts on the rate of relapse or outcome. Patients with systemic AL amyloidosis who received upfront treatment with either oral cyclophosphamide, thalidomide and dexamethasone (CTD) or oral melphalan-dexamethasone (Mel-Dex), with a creatinine clearance of >30 ml/min and who achieved a complete serum free light chain response were identified from the database of the UK National Amyloidosis Centre. NT pro-BNP levels alongside renal and cardiac function were analysed at the 0, 6 and 12 months after commencement of chemotherapy. A total of 51 such patients identified. CTD was administered to 42 of these patients, Mel-Dex to the remaining 9 patients. A rise in NT Pro-BNP from baseline was seen in 36 (71%) patients at 6 months. The median NT pro-BNP increased from a baseline of 106pmol/L at 0 months to 194pmol/L at 6 months (median increase of 163pmol/L; p = 0.0001). A subsequent fall in their NT Pro-BNP levels was seen at 12 months in 33 (92%) of these patients to a median NT Pro-BNP value of 92pmol/L (median fall 157pmol/L; p = There was no significant rise in the creatinine at six months (p=0.439), suggesting that the rise in NT Pro-BNP was not due to a change in the renal function. None of the patients showed a significant change in the left ventricular wall thickness, systolic or diastolic function on echocardiography at 6 months. There was no difference in the rate of NT Pro-BNP rise when comparing the treatments received: 6/9 (67%) of Mel-Dex treated patients and 30/42 (71%) CTD treated patients experienced this NT Pro-BNP rise at six months. At a median follow-up of 29 months, there was no difference in the overall survival and the rate of clonal relapse was identical (44%) for patients who did and did not have an NT Pro-BNP rise at 6 months. In conclusion, this series clearly shows that NT Pro-BNP values can rise transiently in the immediate post chemotherapy period in nearly three-quarters of patients with a complete FLC response. The exact mechanism for this is unclear. This rise is not associated with decline in cardiac function on echocardiography nor is it related to worsening renal function. It does not impact the rate of clonal relapse or overall survival. Given that fluid retention is a known side effect of thalidomide in amyloidosis, one could speculate that thalidomide could cause this transient rise in NT Pro-BNP. However, there was no difference in the percentage number of patients with a rise in NT Pro-BNP between the CTD and Mel-Dex groups (although numbers were very small in the latter group). Further data is needed for non-thalidomide based regimes to assess if this effect is seen to the same extent. This important but transient phenomenon can confound interpretation of treatment response. Immediate post treatment values should be reviewed carefully prior to being used for assessment of organ function or to be used as basis of treatment decisions. Disclosures Off Label Use: Off-label use of thalidomide.

Abstract 1863 Poster Board I-888 The role of thalidomide maintenance has been the subject of much debate in the setting of multiple myeloma, however its use in AL amyloidosis has not been previously reported. We report our experience with thalidomide maintenance in patients who had previously received risk adapted cyclophosphamide, thalidomide and dexamethasone chemotherapy (CTD) for the treatment of AL amyloidosis, specifically examining its relationship to clonal response, time to clonal progression, overall survival and toxicity. All patients who achieved either a partial (PR) or complete response (CR) to CTD between 2002 – 2008 were identified from the database of the UK National Amyloidosis Centre, London and included in this study. Clonal and organ involvement and responses were assessed according to international consensus criteria for AL amyloidosis (Gertz et al, 2005). Progression-free (PFS) and overall survival (OS) was assessed by the method of Kaplan-Meier (KM) both for patients who did and did not receive thalidomide maintenance after a clonal response to CTD. PFS was defined as time to clonal progression after commencement of CTD. Thalidomide maintenance was defined as ongoing treatment with single agent thalidomide after CTD. The total number of patients achieving a clonal response to CTD was 108. Thalidomide maintenance was administered to 25 patients (23%), including 6 patients (24%) with symptomatic myeloma. Of these 25 patients, males accounted for 40%. The median age was 60 years (range 42–77). Median number of organs with AL amyloidosis involved was 2. Before thalidomide maintenance, 11 patients had achieved a CR with CTD (44%) and 14 had achieved a PR (56%). The median number of cycles of CTD administered before thalidomide maintenance was 4.5 (range 1 – 7). The median dose of thalidomide administered as maintenance treatment was 50mg daily (range 50mg alternate days to 200mg daily). The median length of maintenance was 10 months (range 1–70 months). Toxicity was the most common reason for cessation of maintenance treatment. After thalidomide maintenance, only 2/14 patients had an improvement in clonal response (14%). One patient had converted a near complete remission (nCR) to CR and another had converted a serum free light chain (FLC) PR to an FLC CR, but without a whole paraprotein response. Clonal progression was seen in 3/25 (12%) patients during thalidomide maintenance treatment, with another 7 patients relapsing after thalidomide was ceased (10 patients (40%) in total). Organ responses were seen in 3 patients - 2 cardiac and one liver - however these patients were already in a clonal CR after CTD treatment before thalidomide maintenance. 19 patients had stable organ involvement with AL amyloidosis. Organ disease progression was seen in 3 patients. Grade 2 or greater toxicity was reported in 18/25 patients (72%) with neuropathy the most common symptom, reported in 10/25 (40%) patients. All but one patient experienced new onset neuropathy after 10 months of thalidomide maintenance. The median follow-up of the thalidomide maintenance patients was 27 months (range 8–71 months). The median KM estimated OS was not reached for patients who either received CTD alone or with thalidomide maintenance. The median PFS was 33 months for patients treated with CTD alone, whereas this had not yet been reached for those treated with thalidomide maintenance (log rank p = 0.55). In conclusion, thalidomide maintenance after CTD in AL amyloidosis is associated with a high rate of additional toxicity (72%) with only minor improvements in clonal responses (14%) and no improvement in overall survival. There is a suggestion that thalidomide maintenance may delay clonal progression however. The optimal dose for thalidomide maintenance is unknown. While this study is small, we suggest that thalidomide should not be routinely used as maintenance therapy in AL amyloidosis. In selected patients who achieve a good clonal response to CTD and tolerate this chemotherapy well, there may be an argument for thalidomide maintenance if a prolongation in PFS is desired. Agents with less toxicity such as lenalidomide might be preferable and need to be further examined in the maintenance setting. Patients with CTD only Patients with CTD and thalidomide maintenance Number patients 83 25 Males 63% 40% CR at end of CTD 41% 44% Median PFS 33 months Not yet reached Further clonal response with thal maintenance NA 14% Grade 2 + toxicity with thal maintenance NA 72% Disclosures: Off Label Use: Off-label use of thalidomide.

745 The treatment of AL amyloidosis has evolved rapidly over the last few years. The role of autologous stem cell transplantation is controversial and oral combination chemotherapy is often the treatment of first choice. The optimal induction regime is not uniformly agreed upon although some consider oral Mel-Dex as the current “standard of care”. We report our large experience with both Mel-Dex and CTD as upfront treatment for AL amyloidosis in a comparative retrospective study and compare these findings with those of our smaller prospective randomized trial (UKATT), also to be presented as this meeting, using the same treatment regimens (Gillmore et al ). Patients treated with Mel-Dex and CTD as first-line treatment between 2002–2009 were identified from the database of the UK National Amyloidosis Centre, London. Organ involvement and responses were assessed according to international consensus criteria (Gertz et al , 2005). The results are summarised below. Our CTD experience has previously been reported at this Congress (Gibbs et al , 2008). A total of 58 patients received Mel-Dex and 122 patients received CTD as upfront therapy. The baseline characteristics of the two groups were not significantly different in terms of median number of organs involved (by both consensus criteria and 123I labelled serum amyloid P component (SAP) scintigraphy), cardiac involvement, creatinine clearances (CrCl)

The Hyper-CVAD chemotherapy regimen (JCO2000;18:547) is being increasingly applied to a number of haematological malignancies. We have previously demonstrated Hyper-CVAD to be a highly stem cell toxic regimen which adversely affects peripheral blood stem cell (PBSC) mobilisation and that mobilising efficiency can be significantly improved by collecting PBSC earlier in the treatment course. We now examine the optimal timing of PBSC collection when using this regimen. A retrospective analysis was performed at two centres of consecutive patients (pts) treated with Hyper-CVAD in whom an attempt was made to collect PBSC. The regimen consists of alternating cycles of: (A) cyclophosphamide 300mg/m2 q12hrs for 6 doses d1-3, vincristine 2mg d4&11, doxorubicin 50mg/m2 d4 and dexamethasone 40mg daily d1-4 and d11-14; and (B) methotrexate 1g/m2 over 24 hours d1 and ara-C 1–3g/m2 q12hrs for 4 doses d2&3. PBSCs were collected on recovery from chemotherapy using G-CSF in a daily dose of 10mcg/kg. Target cell number for optimum engraftment was defined as CD34 ≥5 x106/kg, while the minimum threshold for proceeding to ASCT was CD34 ≥2 x106/kg. Pts were analysed according to the timing of mobilisation. 74 pts were identified: median age 44yrs; 69% male; 53% with initial marrow involvement; diagnoses (ALL n=14, lymphoblastic lymphoma n=7, Burkitt’s/Burkitt-like lymphoma n=8, aggressive NHL n=34, mantle cell lymphoma n=11). 28 pts were mobilized off the back of cycle A, 32 pts off the back of cycle B, and 14pts after other mobilising regimens. Overall 66% and 42% of pts obtained a minimum and optimal PBSC collection, respectively. Only 3 of 17 patients (18%) collected beyond cycle 3B successfully mobilised. Two patients mobilised prior to 3B but receiving alternate mobilising chemotherapy were not analysed. The results of stem cell collection on the 55 remaining patients are shown below. Stem cell collection results following hyper-CVAD chemotherapy Timing of stem cell mobilisation Cycle 1B 2A 2B 3A N 13 21 14 7 Total CD34+ (range) 21.36 (4.2–69.1) 3.41 (0–11.18) 5.1 (0–22.3) 4.6 (1.9–8.6) Day of 1st apheresis 12 (11–13) 13.5 (11–16) 13.5 (12–19) 15 (13–19) % with CD34+≥2 x106/kg All patients 100% 81% 64% 86% Obtained in 1 apheresis 92% 19% 36% 14% % with CD34+≥5 x106/kg All patients 92% 38% 50% 39% Obtained in 1 apheresis 77% 0% 21% 0% Cycle 1B compared to 2A was not significantly better in obtaining a minimum graft (100% vs. 81%, p=0.14), but was superior in terms of total CD34+ yield (21.4 vs. 3.4x106/kg, p

Background. Alemtuzumab is an increasingly utilized salvage therapy for refractory and/or relapsed B- and T-cell lymphoproliferative disorders with response rates of ~35%. Therapy has been associated with significant infectious and haematologic toxicity. Multilineage cytopenias are a recognised complication, but have been described mostly among patients with CLL and are transient. We report four of twelve (33%) patients treated with alemtuzumab for T-cell lymphoproliferative disorders with unexpectedly prolonged multilineage cytopenias (4 - 11+ months) including two cases of marrow aplasia and one of definitive clonal myelodysplasia. Methods. Patients received the standard alemtuzumab schedule (Eur J Haematol71:250, 2003) of one dose of 3mg IV on d1,10mg on d3 and 30mg on d5, then 30 mg thrice weekly for 12 weeks. Cytomegalovirus (CMV) PCR was performed in all cases of fever, or pancytopenia. Haematologic toxicity was graded according to the NCI Common Toxicity Criteria. Results. 11 patients with advanced (IIB-IV) relapsed and/or refractory cutaneous T-cell lymphomas and one with T-cell PLL were treated. The median age was 55 years (range 29 – 69) and the median number of previous treatments was 4 (range 0 – 17). The median cumulative dose of alemtuzumab was 333mg (range 98–1056). Five patients (42%) experienced grade IV ( 2 months, some never recovering before their death, or with persisting cytopenias during follow-up. The fifth patient died five weeks after starting alemtuzumab with pancytopenia and progressive disease. Four had confirmed CMV reactivation. Neutropenia occurred within 2 weeks of reactivation and in 2 patients, pancytopenia occurred before ganciclovir commenced. One patient who did not experience prolonged pancytopenia had CMV reactivation. One had evidence of chronic parvovirus P19 infection and none had evidence of haemophagocytosis. Discussion. In our series, the alemtuzumab-associated cytopenias were more prolonged than previously described. In four patients, recovery occurred well after the expected two weeks. Two had evidence of marrow aplasia, one of whom died soon after this diagnosis; the other is alive, remaining pancytopenic and transfusion dependent at 14+ weeks after treatment. A third patient was diagnosed with myelodysplasia (cytogenetics: 45X, Y(8)/46, XY (12)), never recovering normal counts, now 12 months post treatment. There was no difference in the liklihood of developing cytopenias in terms of age, sex or dose of alemtuzumab and the pancytopenia never heralded disease recurrence. The exact mechanism of alemtuzumab-associated haematologic toxicity remains elusive. While prolonged lymphopenia is expected, pancytopenia is unexpected since neither haematopoietic stem cells (CD34+) nor more mature myeloid or erythroid cells or megakaryocytes express CD52. We believe the prolonged cytopenias observed were partially a direct effect of alemtuzumab as we excluded infective causes such as parvovirus P19 in four of the five patients and haemophagocytosis in all. Whether the CMV reactivation is involved in the development of, or prolongs the duration of the cytopenias is unknown and further study into the link between CMV and alemtuzumab in the advent of cytopenias in T-cell lymphoproliferative disorders is warranted.

ObjectivesThis study was devised to describe the different cardiac magnetic resonance (CMR) appearances in light chain amyloid (AL) and transthyretin-related amyloidosis (ATTR).BackgroundCMR is increasingly used to investigate patients with suspected amyloidosis. Global subendocardial late gadolinium enhancement (LGE) has been reported as typical of AL amyloidosis, whereas different patterns have been noted in ATTR amyloidosis.MethodsWe performed de novo analyses on original DICOM magnetic resonance imaging in 46 patients with cardiac AL amyloidosis and 51 patients with ATTR type who had been referred to a specialist amyloidosis center between 2007 and 2012 after CMR. Histological examination was performed in all cases, with immunohistochemistry, to confirm systemic amyloidosis.ResultsPatients' median age was 68 ± 10 years, and 74% were male. Left ventricular mass was markedly increased in ATTR amyloidosis (228 g [202 to 267 g]) compared with AL type (167 g [137 to 191 g]) (p < 0.001). LGE was detected in all but 1 cardiac amyloidosis patient (AL type) and was substantially more extensive in ATTR compared with AL amyloidosis. Ninety percent of ATTR patients demonstrated transmural LGE compared with 37% of AL patients (p < 0.001). Right ventricular LGE was apparent in all ATTR patients but in only 33 AL patients (72%) (p < 0.001). Despite these findings, survival was significantly better in cardiac ATTR amyloidosis compared with AL type. We derived an LGE scoring system (Query Amyloid Late Enhancement) that independently differentiated ATTR from AL amyloidosis and, when incorporated into a logistic regression model with age and wall thickness, detected ATTR type with 87% sensitivity and 96% specificity.ConclusionsTransmural patterns of LGE distinguished ATTR from AL cardiac amyloidosis with high accuracy in this real-world analysis of CMR. Precise diagnosis of cardiac amyloidosis is crucial given the role of chemotherapy in AL type and with novel therapies for ATTR type currently in development.

Abstract 947 Background: Many patients with sickle cell disease have decreased functional capacity as measured by the six-minute walk (6MW) test compared to controls; however, there is considerable variability in exercise performance among the patients themselves[1, 2]. To date, the 6MW test has not been evaluated in a large cohort of adult sickle cell anemia patients. Methods: Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) includes an on-going observational study of sickle cell disease patients at nine United States Centers and one United Kingdom Center. In the screening phase of the study, patients had clinical evaluation, echocardiography and 6MW testing performed. Of 720 patients screened, 483 had hemoglobin SS phenotype. To investigate potential prognostic predictors for decreased exercise capacity, we analyzed, among patients with hemoglobin SS, the relationship of baseline clinical characteristics with 6MW distance (6MWD). The Doppler-echocardiographically measured tricuspid regurgitation velocity (TRV) estimates right ventricular systolic pressure, and left ventricular lateral wall E/Ea ratio estimates left ventricular filling pressure. Walk-PHaSST prospectively defined 3 patient cohorts based on screening TRV: < 2.7 m/sec, 2.7–2.9 m/sec and ≥3.0 m/sec. Results: Of 483 hemoglobin SS patients, the median age was 35 years (range 12 to 69 years) and the gender split was 250 females to 233 males. The 6MWD was measured in 475 patients, TRV was measured in 453, LV lateral wall E/Ea was measured in 436 and hemolytic component was calculated in 406. The median 6MWD was 438 m (inter-quartile range of 383–504 m and overall range of 123–711 m). TRV was 2.7–2.9 m/sec in 22% and ≥3.0 m/sec in 17%. By linear regression, female gender was independently associated with an estimated 44 m decrease in 6MWD (95% CI of 27–61 m; P In a pathway analysis, higher TRV and LV lateral wall E/Ea ratios were directly associated with decreased 6MWD. Elevated creatinine, higher hemolytic component and degree of anemia were not associated with 6MWD. However, elevated creatinine was directly associated with both higher TRV and lateral wall E/Ea ratios, and elevated hemolytic component was directly associated with higher TRV. Conclusion: In this prospective multicenter, international study of patients with sickle cell anemia, we found higher estimated: 1) right ventricular systolic pressure, and 2) left ventricular filling pressure (as determined by Doppler-echocardiography) to be independently associated with decreased functional capacity, after adjusting for gender and age. These data suggest that cardiac dysfunction may contribute to impaired exercise capacity in sickle cell anemia. These studies suggest that the 6MW test may be an appropriate endpoint for controlled studies directed at improving cardiac function in patients with sickle cell anemia. References: 1. Gladwin, M.T., et al., Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med, 2004. 350(9): p. 886–95. 2. Minniti, C.P., et al., Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica, 2009. 94(3): p. 340–7. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Kato:Ikaria-INO Therapeutics: Research Funding, Research Funding as part of a CRADA (Cooperative Research and Development Agreement with NIH). Hassell:Novartis: Research Funding. Badesch:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gladwin:Ikaria-INO Therapeutics: Research Funding, With NIH through a Cooperative Research and Development Agreement.

Background Involvement of the heart drives prognosis in Systemic AL Amyloidosis, predicting outcome and influencing therapeutic options. Current methods of cardiac assessment do not allow formal quantification of the amyloid load. We used Equilibrium Contrast Cardiovascular Magnetic Resonance (EQ-CMR) to measure the interstitial compartment of the heart by measuring the myocardial contrast volume of distribution, VDm.