Go, Ronald S.

Abstract Background Bendamustine/rituximab (BR) and dexamethasone/rituximab/cyclophosphamide (DRC) combination therapy are acceptable options for the treatment of WM, both in the frontline or salvage setting. Prospective data, however, are only available in treatment-naïve (TN) WM patients, and no direct comparison between BR and DRC has been reported. We compared outcomes of BR and DRC in relapsed/refractory (R/R) and TN WM patients seen at a single institution. Methods Records of WM patients seen consecutively at Mayo Clinic from 01/2007 to 12/2014 were reviewed. The MYD88L265P status, as assessed by AS-PCR, was recorded when available. The data obtained from symptomatic patients treated with DRC or BR were analyzed. The time-to-event analyses were performed from DRC or BR therapy using the Kaplan-Meier method. We used the Consensus criteria (6th International Workshop) for response assessment. Results Of 160 WM patients, 60 patients received BR (73% in R/R setting) and 100 patients received DRC (50% in R/R setting). In the R/R population, BR was the 2nd line (range 2-11) therapy in 47% of patients, while DRC was 2nd line (range 2-8) in 58% of patients. Rituximab monotherapy was the only prior line of therapy in 8 (20%) patients in the BR group and 20 (40%) in the DRC group (p=0.66). Baseline characteristics were similar in patients treated with BR or DRC (Table 1). Six patients received both BR and DRC during their disease course and overlapped between the 2 cohorts. Among the previous untreated patients, the median IgM levels decreased from 3,785 mg/dL to 724 mg/dL (p=0.0001) at best response with BR, while it decreased from 4,130 mg/dL to 1,250 mg/dL (p=0.001) with DRC. The median time to best response was 6.1 (1-25) months in the BR group and 11 (0.5-47) months in the DRC group (p=0.13). For patients treated with BR, the overall response rate (ORR) was 93% [VGPR 29% (n=4), PR 57% (n=8), MR 7% (n=1)]. One patient (7%) had progressive disease. For patients treated with DRC, ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. One patient (4%) achieved SD. Median follow up in the BR and DRC groups were similar (30 months). The 2-year progression-free survival (PFS) was 88% and 61% in the BR and DRC groups, respectively (p=0.08). The 2-year time-to-next therapy (TTNT) was 88% and 76% in the BR and DRC groups, respectively (p=0.35). Median PFS, TTNT and disease specific survival (DSS) were not reached with either regimen. In the R/R setting, the median IgM levels decreased from 3,880 mg/dL to 659 mg/dL (p=0.0001) at best response with BR, and from 3,870 mg/dL to 1,846 mg/dL (p=0.001) with DRC. The median time to best response was similar [7 (1-39) months with BR and 7 (0.5-28) months with DRC (p=0.77)]. For patients treated with BR, ORR was 95% [CR 3% (n=1), VGPR 38% (n=14), PR 41% (n=15), MR 13% (n=5)]. Two patients (5%) had progressive disease. With DRC, the ORR was 87% [VGPR 4% (n=2), PR 64% (n=30), MR 19% (n=9)]. Four patients (9%) achieved SD and 2 patients (4%) had progressive disease. Median follow up from BR was 32 months and 51 months from DRC (p=0.24). The 2-year PFS was 66% and 53% in the BR and DRC groups, respectively (p=0.08). The 2-year TTNT was 75% and 68% in the BR and DRC groups, respectively (p=0.24). The median DSS in the BR group was 69 months (95% CI: 65-69) and NR (95% CI: NR-NR) in the DRC group (p=0.57). The proportion of patients with R/R disease was significantly higher in the BR cohort (Table 1). In a bivariate analysis of the entire cohort for PFS, incorporating the setting (TN vs. RR) and the regimen involved (BR vs. DRC), the latter emerged as a significant factor (hazard ratio 0.52, p=0.019) in favor of BR. Time-to-event outcomes and response rates were similar in the MYD88L265P and MYD88WT patients. Grade ≥ 3 adverse events were neutropenia (12%), infections (7%) and nausea/vomiting (2%) with BR, and neutropenia (20%), thrombocytopenia (7%) and infections (3%) with DRC. Conclusions Although both DRC and BR regimens show activity and comparable toxicities, BR regimen shows a trend for superior PFS in WM patients, both in the TN and R/R setting. No difference was seen in TTNT. MYD88 L265P mutation status does not appear to impact activity of BR or DRC. Randomized controlled trial(s) are needed to confirm our findings. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

Abstract Background: Unlike acute lymphoblastic leukemia, data on acute myelogenous leukemia (AML) in the adolescents and young adults (AYA) are limited and generally derived from clinical trials, which are mostly conducted in academic centers. It is unclear whether the choice of treatment facility influences clinical outcome independent of disease biology and socio-demographic factors. This study used the National Cancer Data Base, a nationwide oncology database covering 70% of the US cancer population, to address this question. Methods: We identified 11,712 AYA patients who were diagnosed with AML from 2003-2011. We excluded patients who were: a) 15-17 years of age (n = 3,104) as treatment facility data were not available for age <18 years; b) not treated at the reporting facilities (n = 415) as follow-up might be incomplete; c) treated at treatment facilities with ≤100 new cancer cases/year (n = 18); and d) those without follow-up data (n = 47). Treatment facilities were classified as academic, comprehensive community (>500 new cancer cases/year), or community (101-500 new cancer cases/year) cancer programs. AMLs harboring t(15;17), inv(16), or t(8;21) were defined as good-risk, while the rest were considered non-good risk. Overall survival from the time of AML diagnosis was the primary outcome. We used multivariate imputation by chained equation to impute missing values, weighted Cox regression to obtain average hazard ratios (HRs), and pooled Wald c2 statistics to detect interaction. Results: We included 8,128 AYA patients with AML in the study and 25.2% were good risk. Among the good risk AMLs, 11.6%, 12.3%, and 76.1% had t(8;21), inv16, and t(15;17), respectively. The distribution of patients by treatment facility were academic (64.1%), comprehensive community (32.9%), and community (3.0%). After detecting an interaction between AML risk and type of treatment facility (P=0.038), we stratified treatment facility by AML risk and found significant differences in overall survival among good risk (P=0.02) but not non-good risk AML (P=0.19). This survival difference persisted even after adjusting for demographic (age, sex, race/ethnicity), socioeconomic (income, education, medical insurance), geographic (area of residence, travel distance), co-morbidities (Charlson-Deyo score), and treatment (receipt of chemotherapy) factors. Patients with good risk AML treated in comprehensive community cancer programs had a higher risk of death compared to those treated in academic programs (adjusted HR: 1.41, 95% CI: 1.11-1.79). For community cancer programs, the risk of death was also higher but did not reach statistical significance (adjusted HR: 1.22, 95% CI: 0.68-2.21). ). Subset analysis showed that the survival difference among those with good risk AML was observed in t(15;17) or acute promyelocytic leukemia (APL; P=0.02) but not in t(8;21) or inv16 (P=0.79). The disparity occurred primarily during the first month of APL diagnosis, wherein the risk of death was two-fold higher in community programs (Figure). Conclusions: Among AYA patients with AML, treatment at academic cancer programs was associated with a better survival, but only for the APL subgroup. Because APL comprises a fifth of all AMLs in the AYA and is a highly curable cancer, health care delivery research in APL should become a priority in this age group. Figure 1. Figure 1. Disclosures Al-Kali: Celgene: Research Funding.

Abstract BACKGROUND: Necrobiotic Xanthogranuloma (NXG) is a rare chronic granulomatous disorder of the skin associated with monoclonal gammopathies (MG). Due to its rarity, data on response to various therapies are largely limited to single case reports or small case series. Hence, we described the clinical features in patients with NXG and MG as well as their subsequent disease course and response to treatment. METHODS: This was a retrospective study evaluating 35 patients with NXG and coexisting MG from 1994-2015 who were evaluated in the Hematology Outpatient Clinic at the Mayo Clinic, Rochester. All patients had a biopsy proven diagnosis of NXG with the concurrent presence of a serum monoclonal gammopathy. RESULTS: The median age at diagnosis was 56 years (range: 26-88). Most patients had a plasma cell dyscrasia (28 MGUS; 5 Smoldering myeloma) while 2 had chronic lymphocytic leukemia. Themost common monoclonal (M) protein was IgG kappa (60%). The median M-spike was 1.1 g/dL (range: 0-3). The most common site of NXG was periocular (66%). All patients received treatment, with over half requiring >3 different lines of treatment. The treatments were heterogeneous and included excision, intra-lesional injection, radiotherapy as well as systemic treatment. The types of systemic treatment used and clinical response are reported in Table 1. The median follow up was 46 months (range: 4-234) and the median survival was not reached but at the time of analysis 80% were still alive. At last follow-up, 80% of patients had signs of either clinical improvement or stable skin disease. Eight patients (23%) had disease progression to multiple myeloma at a median of 67 months (Range: 21 - 107). CONCLUSIONS: We report the clinical findings and treatment outcomes of one of the largest series of patients with NXG associated with MG. The clinical course is generally indolent but malignant transformation is not uncommon. Cutaneous objective responses can be achieved with various systemic agents used in the treatment of lymphoproliferative malignancies. Table 1. Treatment Types and Clinical Response Rates Treatment No of patientsA Clinical Benefit Rate B Response rateC Chemotherapy - Chlorambucil +/- Steroids - Melphalan/Steroids - Cytoxan/Steroids - Cladribine - Vincristine/doxorubicin/dexamethasone - High dose therapy with stem cell rescue - Fludarabine/cyclophosphamide/rituximab 5 3 4 3 2 3 1 2/5 (40%) 0/3 (0%) 1/4 (25%) 1/3 (33%) 1/2 (50%) 2/3 (67%) 1/1 (100%) 1/5 (20%) 0/3 (0%) 0/4 (0%) 1/3 (33%) 0/2 (0%) 2/3 (67%) 1/1 (100%) Novel agents - Thalidomide +/- Steroids - Lenalidomide +/- Steroids - Bortezomib +/- Steroids - Bortezomib/Lenalidomide/Dexamethasone 11 14 4 1 5/11 (45%) 10/14 (71%) 2/4 (50%) 1/1 (100%) 4/11 (36%) 7/14 (50%) 1/4 (25%) 1/1 (100%) Intravenous immunoglobulin 4 3/4 (75%) 2/4 (50%) Systemic steroids alone 11 4/11 (36%) 4/11 (36%) Rituximab 6 2/6 (33%) 1/6 (17%) AntibioticsD 3 0/3 (0%) 0/3 (0%) ImmunosuppressantsE 6 1/6 (17%) 0/6 (0%) ANo of patients who underwent a particular therapy amongst the 35 patients in the study cohort. BClinical Benefit: Improvement or stable skin disease CResponse: Improvement in skin disease DAntibiotics: Fluoroquinolones, Tetracycline EImmunosuppressants: Cyclosporine, Methotrexate, Plaquenil Disclosures Kumar: Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Skyline, Noxxon: Honoraria.

Abstract Background: Ixazomib is an experimental, orally bioavailable, proteasome inhibitor that has demonstrated anti-tumor activity in relapsed multiple myeloma (MM). In the dose escalation studies, ixazomib was tolerated up to a dose of 5.5 mg given every week as a single agent, while a dose of 4 mg was utilized in the combination studies with lenalidomide. We undertook this study to examine the efficacy and tolerability of the two doses of ixazomib in combination with dexamethasone in patients with relapsed MM. Patients and methods: This was a randomized phase 2 study of two doses of ixazomib (4mg; Arm A or 5.5 mg; Arm B) given weekly for three weeks with a week off along with weekly dexamethasone (40 mg) in patients with relapsed MM, who are proteasome inhibitor na•ve (including bortezomib) or have received less than 6 cycles of therapy with bortezomib and had a PR or better with no progression at the time of discontinuation. The primary objective was to determine the confirmed overall response rate (>=PR); secondary objectives included progression free and overall survival. A total of 71 patients were accrued from February 2013 to April 2015; one patient was ineligible. Results: Baseline characteristics were similar in the two arms; median age across the study was 70 years (46-84); 53% were male. Median number of prior therapies was 4 (range 2-6); 90% of the patients had prior IMiDs, 70% had prior transplant and 29% had prior bortezomib. At a median follow up of 10 months, 17 (49%) and 19 (54%) of patients had disease progression in arms A and B respectively with 12 (34%) patients in each arm still continuing on treatment. All patients in each arm were evaluable for response; the overall response rates were 31% in arm A (95%CI: 17-49) and 51% (95%CI: 34-69) in Arm B. The depth of response, event free survival and overall survival are outlined in Table 1. Among the patients with no prior bortezomib exposure the response rates were 38% for Arm A and 52% for Arm B. The treatment was well tolerated with 2 patients in each arm discontinuing treatment for adverse events; there were no on study deaths. A grade 3 or higher AE that was at least possibly related to treatment was seen in 21% and 54% in Arms A and B respectively; with 15% and 37% hematologic and 6% and 29% non-hematologic AEs. The most common attributable toxicities encountered included fatigue, thrombocytopenia, diarrhea and nausea with more grade 3 toxicities among Arm B. Peripheral neuropathy, possibly related to ixazomib, was seen in 55% (only grade 1 or 2) in arm A and 43% (2 patients with grade 3) in Arm B. Toxicities led to dose reduction of ixazomib in 17% and 43% of patients in Arm A and B respectively; the median number of cycles administered were 5 (1-24) and 5 (1-22) respectively. Conclusions: Ixazomib in combination with dexamethasone was well tolerated with significant anti-myeloma activity in this group of patients with relapsed MM. Deep responses including stringent CR were observed. The higher dose of ixazomib appears to be associated with a higher response rate but with higher rate of adverse events requiring dose reductions. Table 1. Treatment outcome in all patients Arm B (4 mg) (N=35) Arm C (5.5 mg) (N=35) Response Rate 31% (95%CI: 17-49) 51% (95%CI: 34-69) No. of Responders 11 18 sCR 0 1 CR 1 0 VGPR 7 8 PR 3 9 MR 5 1 Median Overall Survival1 NA NA 6 Months 100% 100% Median Event Free Survival1,2 8.4 mos (95%CI: 4.3-13.2) 8.2 mos (95%CI: 3.8-16.3) %Event Free at 6 Months 60% (95%CI: 45-81) 60% (95%CI: 45-81) Median Duration of Response1 16.7 mos (95%CI: 9.3-22.0) 16.3 mos (95%CI: 7.0-20.1) Median Time to Response 1.1 mos (range: 0.8-3.6) 1.0 mos (range: 0.8-7.5) CI: confidence interval; mo: month; NA: not attained 1Kaplan Meier 2Event-free survival time is defined as the time from registration to the first of disease progression, death due to any cause, or subsequent treatment for multiple myeloma. Disclosures Kumar: Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy.

Abstract Background: Cytogenetic evaluation, especially using fluorescence in situ hybridization (FISH), at the time of diagnosis is essential for initial risk stratification and the employment of risk-adapted treatment strategies in multiple myeloma. Little is known about the occurrence and prognostic significance of cytogenetic evolution during follow up. Methods: We studied 433 patients who were diagnosed with multiple myeloma between January 2000 and December 2011 and had at least two FISH evaluations at Mayo Clinic Rochester, including the diagnostic specimen. Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Cytogenetic evolution was defined as a new deletion, monosomy, trisomy, tetrasomy, or translocation during follow up. Multivariable-adjusted logistic regression models were used to assess the associations between the parameters of interest and the presence of cytogenetic evolution in follow-up specimens. Multivariable-adjusted Cox proportional hazards models were used to assess the effect of cytogenetic evolution on overall survival. All models were adjusted for sex, age, the presence of high-risk FISH abnormalities, and the number of abnormalities at the time of diagnosis. Likelihood ratio tests were used to assess the goodness of fit of nested models. The χ2 or Fisher's exact test was used to assess the distribution of cytogenetic abnormalities in subgroups. Results: The median age at diagnosis was 60 years (32 - 82), 264 (61%) of the patients were male. The median overall survival for the entire cohort was 7.0 years (6.2 - 7.8). At the time of diagnosis, 150 (35%) and 57 (13%) of the 433 patients presented with a hyperdiploid karyotype and cytogenetic high-risk abnormalities, respectively. Independent of each other, the presence of a translocation at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow up (OR 0.39, 95% CI 0.24 - 0.63, p < 0.001) while the presence of at least one trisomy or tetrasomy at the time of diagnosis was associated with increased odds (OR 2.53, 95% CI 1.37 - 4.70, p = 0.003). A greater proportion of patients presenting with a hyperdiploid karyotype experienced cytogenetic evolution during follow up. Those patients more frequently evolved additional trisomies and tetrasomies, while translocations were more common in those presenting with a non-hyperdiploid karyotype (Table 1). The development of additional abnormalities during the three years following diagnosis (compared to no new abnormalities) was associated with increased subsequent mortality in those who survived at least three years (HR 3.22, 95% CI 1.82 - 5.68, p < 0.001). Including the time between first and last cytogenetic evaluation as a covariate did not significantly change the parameter estimates or improve model fit (p = 0.727). Conclusions: Demographics, risk profile, and overall survival of this cohort reflect the fact that patients had to survive long enough to undergo repeated cytogenetic evaluation. Hyperdiploid and non-hyperdiploid genotypes were associated with distinct behavior regarding cytogenetic evolution during follow up. The identification of cytogenetic evolution was an adverse prognostic factor in those who survived at least three years after diagnosis. These findings emphasize the importance of the dynamics of the underlying clonal disease process for accurate risk assessment and suggest that selected subgroups of patients may benefit from risk stratification during follow up. Table 1. Cytogenetic evolution during follow up in 433 patients with multiple myeloma stratified by karyotype at the time of diagnosis Hyperdiploid (n = 150) Non-hyperdiploid (n = 283) p New abnormality 76 (51%) 108 (38%) 0.012 New monosomy 8 (5%) 24 (8%) 0.243 New trisomy 48 (32%) 55 (19%) 0.004 New tetrasomy 37 (25%) 27 (10%) < 0.001 New deletion 17 (11%) 27 (10%) 0.557 New translocation 1 (1%) 11 (4%) 0.065 Most common new abnormality [type (percent of type in each group)] Monosomy mono(13) (75%) mono(13) (62%) Trisomy tri(11) (22%) tri(3) (22%) Tetrasomy tetra(15) (48%) tetra(15) (30%) Deletion del(17p) (79%) del(17p) (63%) Translocation t(11;14) (100%) t(11;14) (36%) Data are given as count (percent) unless denoted otherwise. Disclosures Binder: American Society of Hematology: Research Funding. Kumar:AbbVie: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Abstract Background: Light chain Amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in major organs and/or soft tissue. An observational study on natural history and outcome of localized immunoglobulin light-chain amyloidosis without vital organ (liver, heart, kidney, peripheral and autonomic nervous system) involvement has shown extremely low rate of progression (1%) to systemic amyloidosis at a median follow-up of 74.4 months (Mahmood S et al. The Lancet Haematology; 2015; 6:e241-e250). There is, however, limited evidence in published literature on natural history of AL amyloidosis confined to fat and/or bone marrow biopsy, without involvement of vital organs or other soft tissues. Methods: We retrospectively identified patients with AL amyloidosis limited to fat and/or bone marrow aspirate in a single-institution database. Patients were evaluated for progression to systemic amyloidosis. Statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.). Results: We identified 117 patients, with a median age of 70 years, who had light chain amyloidosis detected in abdominal fat aspirate and/or bone marrow biopsy, without systemic involvement. Amyloid was seen in fat only in 39%, marrow only in 54% and in both sites in 7%. The median follow up was 45.6 months (95% CI-38.1-57.7) from detection of amyloid. Of these, 64% were alive at the time of analysis. Among 117 patients, 65 were treated for a diagnosis of another plasma cell disorder made prior to or concurrent with detection of amyloid. The remaining 52 patients only had isolated fat or marrow amyloid. Among 65 patients with another diagnosis of plasma cell disorder requiring treatment, 3 progressed to systemic amyloidosis, one each with cardiac, renal and lymph node (LN) involvement detected at 32, 42 and 65 months respectively from the detection of amyloid. The first 2 patients had underlying multiple myeloma, and the third patient with LN involvement had underlying Waldenström macroglobulinemia. Among 52 patients without another diagnosis of a plasma cell disorder requiring treatment, at a median follow up of 32 months, no progression to systemic amyloidosis was observed. Median overall survival (OS) in 117 patients from detection of amyloid, using Kaplan-Meier survival estimates, was 60.2 months (95% CI-48.9-146.1). Conclusion: Our study highlights the fact that isolated amyloidosis detected in fat and/or bone marrow aspirate, in the absence of another plasma cell dyscrasias that require therapy, is unlikely to progress to systemic amyloidosis. Watchful waiting might be considered in such patients after a thorough evaluation to rule out systemic involvement. Disclosures Gertz: Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Millenium: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Abstract Background: Amyloidosis is a multisystem disease with extracellular deposition of pathological insoluble beta-fibrillar proteins. Involvement of the heart is seen in more than one-half of the patients with systemic AL amyloidosis and it is the most important determinant of clinical outcome. Cardiac amyloidosis is a restrictive infiltrative cardiomyopathy in which, despite declines in stroke volume that accompany disease progression, the ejection fraction (EF) often remains preserved even in advanced stages of the disease. King et al. proposed a novel index of myocardial function, the myocardial contraction fraction (MCF), defined as the ratio of stroke volume (SV) to myocardial volume (MV). MCF is a measure of myocardial shortening, which differentiated myocardial performance in patients with similar degrees of hypertrophy and in a recent small cohort of AL amyloidosis patients appeared superior to left ventricular ejection fraction (EF) in predicting overall survival (OS). It was our goal to assess the prognostic role of MCF in a large cohort of patients with AL amyloidosis in the context of other prognostic variables. Methods: Patients seen between 4/1/1999 and 2/1/2015 were eligible for this retrospective study if they had an ECHO at the Mayo Clinic, Rochester, MN within 30 days of their AL amyloidosis diagnosis with measurements of left ventricular chamber size and wall thickness needed to calculate MCF, EF, and the presence or absence of pericardial effusion. To capture the full cohort, modeling was done first excluding Mayo (2012) staging and global averaged left ventricular longitudinal peak systolic strain (LV strain) since limited numbers of patients had these studies, 342 and 294, respectively. Thresholds of continuous variables were chosen based on receiver operator curves targeting death at 1-year. Cox proportional hazards analysis was used to identify factors that were prognostic for OS. Statistical analyses were done using JMP 9.0 (SAS, Cary, NC). Results: Among the 722 patients satisfying entry criteria,median age was 64 years (range 32-94) and 66% were male. The best cutoff for MCF was 21% (sensitivity: 74%, specificity: 60%; AUC=0.699) and distinguished two groups with different OS (median 53 vs. 9 months, P<0.0001; Figure). On univariate analysis the baseline ECHO variables predicting OS were interventricular septum thickness (IVS) >12 mm (RR 1.8, P=0.0002), EF <60% (RR 1.7), MCF ≤21% (RR 2.1), and presence of pericardial effusion (RR 2.0), all with P<0.0001. On multivariate MCF ≤21% (RR 1.6, P <0.0001), EF <60% (RR 1.4, P=0.0007) and the presence of pericardial effusion (RR 1.3, P=0.002) were independent predictors of OS. Additional modeling was done with the subset of 342 patients who were assessable for Mayo (2012) staging, (i.e. measurements of immunoglobulin free light chain, NT-proBNP, and troponin T). On univariate analysis, patients with a Mayo (2012) stage ≥ 3 had a RR 2.1, p<0.0001. On multivariate, only MCF ≤21% (RR 1.5, P =0.01), Mayo (2012) stage ≥ 3 (RR 1.5, P=0.01) and EF<60% (RR 1.7, P=0.0006) were independent prognostic determinants. Finally, we addressed LV-strain among the 294 patients in whom the study was performed. There was a significant correlation between MCF and LV strain (rho =-0.86, P<0.0001). On univariate, LV-strain less negative than -13 generated a RR of 2.3, p<0.0001. In contrast to the model containing MCF, on LV-strain multivariate, EF was no longer significant, but LV-strain less negative than -13 (RR 2.0, P=0.008) and Mayo (2012) stage ≥ 3 (RR 2.0, P=0.008) predicted independently OS. Conclusions: MCF ≤21% identified a subgroup of patients with a high mortality risk, and it was independent of the Mayo (2012) staging but highly correlated with LV strain. An advantage of MCF, which is a novel volumetric measurement of the left ventricular chamber, is that, unlike LV-strain, MCF is simple to calculate from routine ECHO measures. Figure 1. Overall survival of 722 patients according to MCF<21%. Figure 1. Overall survival of 722 patients according to MCF<21%. Disclosures Kumar: AbbVie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Skyline, Noxxon: Honoraria; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding.

Lymphoproliferative disease of granular T lymphocyte (T-LDGL), also known as T-cell large granular lymphocyte leukemia, is a clonal disorder of cytotoxic T lymphocytes that is clinically manifested as chronic neutropenia and anemia. Association with autoimmune disorders is common. In 9 patients, T-LDGL is reported as presenting as aplastic anemia. The clinical characteristics were similar to acquired aplastic anemia. Morphologic evidence of increased granular lymphocytes in the peripheral blood and an excess of CD3+/CD8+/CD57+ cells in the bone marrow were found in most cases. Cyclophosphamide was ineffective, but noncytotoxic immunosuppressive agents generally produced a good response. After a median follow-up of 49 months, 5 patients had died from the disease or related complications. Median survival was 40 months. Aplastic anemia can be a presenting manifestation of T-LDGL, and T-LDGL should be considered in the differential diagnosis of acquired aplastic anemia.

Abstract Background: American Indians and Alaska Natives (AI/AN) currently represent approximately 2% of the US population. However, population-based cancer studies are generally limited. Utilizing the Surveillance, Epidemiology and End Results Program (SEER), we investigated the incidence, major subtype distribution, and survival of non-Hodgkin lymphomas (NHL) in the AI/NA population. Methods: We queried the SEER 2000-2012 database for AI/AN patients with NHL using ICD-O-3 codes 9590-9823. We calculated their incidence rate (case/1,000,000) and trend as well as risk ratios compared to other races, age-adjusted to the US 2000 standard population. Patient level data were extracted to perform summary statistics and calculate overall survival (OS) using STATA/IC 12.1. Results: We identified 1,135 AI/NA patients with NHL. The average age was 59.6 years (range, 20-85) and 53% were males. The distribution of the major NHL subtypes resembles that seen among the rest of the population and is as follows: diffuse large B-cell (DLBCL; 28%), marginal zone (MZL; 19%), follicular (FL; 13%), small lymphocytic/chronic lymphocytic leukemia (SLL/CLL; 10%), NHL not-otherwise specified (NOS, 4%), mantle cell (MCL; 2%), anaplastic large cell (ALCL; 2%), lymphoplasmacytic (LPL; 1%), and peripheral T-cell (PTCL; 1%). The overall incidence of NHL is 26.4 and did not significantly change over the 12-year study period (Annual Percent Change 0.0, 95% CI [-0.3, 0.3]). Compared to other races, AI/NA have lower incidence of NHL including most of the major subtypes (Table). The median OS for all types of NHL combined is 4.16 years. AI/AN OS is statistically inferior compared to Whites(Figure). Conclusions: The NHLincidence in AI/NA is lowest among the major race groups and has remained stable in the past 12 years. However their OS is inferior when compared to Whites. The distribution of major NHL subtypes and OS are similar to the rest of the population. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background : Celiac disease (gluten sensitive enteropathy) is a systemic disease with hematological manifestations including; iron deficiency anemia, vitamin B12 and folate deficiency, leukopenia/neutropenia, hyposplenism, venous thromboembolism, and the enteropathy associated T cell lymphoma (E-TCL). Leukopenia/neutropenia is rare, and can result from folate or copper deficiency, but in many cases remains idiopathic. The consequences of neutropenia and neutrophil responses to a gluten free diet are not well described. We carried out this study to assess the incidence and outcomes of neutropenia in patients with celiac disease. Methods : The Mayo clinic celiac disease database (n=1729) was retrospectively analyzed for all patients with a confirmed diagnosis of celiac disease that had leukopenia (<3.5 x10(9)/L) and/or neutropenia (<1.5 x 10(9)/L). The diagnosis of celiac disease was established by positive tissue transglutaminase antibodies (TTG) and confirmatory small bowel biopsy findings. Additional causes of neutropenia such as copper and folate deficiency, drugs, benign ethnic and cyclic neutropenia, chemotherapy, hematological malignancies, combined variable immunodeficiency (CVID), and autoimmune diseases were meticulously excluded. Data abstracted included demographics, temporal association with diagnosis, nadir counts, associated hematological findings, relationship with infections, the use and effect of G-CSF, response to gluten free diet and survival outcomes. Results: 21(1.2%) of 1729 cases screened had idiopathic-celiac related neutropenia; 17 (81%) Caucasian, 15 (48%) females. In 12(57%) patients the neutropenia preceded or occurred near the time of the diagnosis of celiac disease, while in 7 (33.3%) it occurred subsequently. In 2 cases the temporal association could not be established. The median age at diagnosis of celiac disease was 46 years (10-67) and the median follow up for this group was 41.7 months (0-207.3). At last follow up 1 (4.8%) death has been documented; 0 from infectious complications, with no cases of E-TCL. The median laboratory values at diagnosis of celiac disease were available in 11 (52%) patients and included; hemoglobin 12.9 g/dL (10.5-16.8), MCV 91.5 fl (79.6-102.8), WBC 3.2 x109/L (2.3-5.2), ANC 1.29x109/L (0.33-3.24), ALC 1.34x109/L (0.75-2.17), AMC 0.39x109/L (0.15-0.71), and platelet counts 225x109/L (168-711). Anti-granulocyte antibodies were assessed in 7 patients and were negative in all cases. None of these patients had coexistent hyposplenism and three cases of neutropenia that occurred in the setting of celiac disease and CVID were excluded. In 15 (71%) patients the neutropenia was incidentally detected during routine laboratory work and in 4 (19%) it came to light secondary to infections. Ten (48%) patients had recurrent infections (≥1) as documented by their providers, including 7 with sinopulmonary infections, 1 with urinary tract infections, and 1 with skin and soft tissue infections. Additional immunological assessments were not available in these patients. Three (14%) patients had an ANC <500 (significant neutropenia); of which 2 had recurrent sinopulmonary infections. The third patient remained largely asymptomatic. Two of the 3 patients received G-CSF support during infections and responded adequately (ANC improvement > 1 x 10(9)/L). The ANC in patients in this cohort did not correlate with severity of infections. Five (23%) of 21 patients had improvement in neutrophil counts after adopting a gluten free diet, while there was no response in 10 and data was unavailable in 6. The median time to ANC response was 14.5 months (10-15.3) and the median increment in ANC was 0.67 x 10(9)/L (0.48-0.98). Conclusions: Celiac disease associated neutropenia, especially significant neutropenia (ANC <500) is a rare occurrence (~1%). It can often pre-date the diagnosis of celiac disease or occur subsequently. It is potentially associated with an increased incidence of infections, with-out good correlation with the severity of neutropenia. Less than half the patients do seem to respond to a gluten free diet. G-CSF responses seem to be adequate and G-CSF can be used in the setting of severe infections. Disclosures No relevant conflicts of interest to declare.