ALBERT

Description: Background Waldenstrom Macroglobulinemia (WM) is a hematological malignancy that affects 1500 people each year in the United States. Due to lack of literature on era comparative population-based analysis, we have analyzed Surveillance Epidemiology and End Results (SEER) data to evaluate the changes in incidence and survival patterns in the new millennium where modern therapeutic agents such as rituximab, immunomodulatory drugs and proteasome inhibitors were offered to WM patients; in contrast to the earlier period when they were non-existent. Methods The SEER 18 registry which includes data from 1973-2010 from 18 geographic areas including 28% of US representative population was used in analysis. ICD-O-3 code 9761 was used for identifying patients for this analysis. SEER* Stat 8.0.4 is used to calculate age-adjusted incidence and mortality rates based on race, gender, and age for patients. Age adjusted rates were used in this anlaysis to avoid confounding variables when comparing rates over time. Results We have included 4304 patients in the analysis (1244 patients diagnosed before 2000 and 3060 patients after 2000). The incidence rate of WM increased with age. The 10 year cumulative incidence rate per 100,000 by age stratification (80) are 0.02%, 0.40%, 1.01%, 2.14% and 2.98% respectively. Over the last decade the trend of incidence rate in WM has been steadily decreasing across all age groups (Figure 1). Median survival for all WM patients is 74 months (m) (70.2-77.8). Significant survival improvement was seen in the current era (median survival ≥2000 vs.

Description: Background: Multiple Myeloma (MM) represents 1.8% of all new cancers in the United States and is the second most common hematologic malignancy in the US with 30,000 new cases/year. The highest incidence is amongst African Americans (AA) (SEER, 2018). Increased use of autologous stem cell transplant (AHSCT) as well as introduction of proteasome inhibitors (PIs) and immunomodulatory agents (iMiDs) have led to an improvement in overall survival (OS) from 35.6% between 1998-2001 to 50.7% in 2008-2014 (Child et al. 2003; Pulte et al. 2014). Despite these improvements, outcomes in MM are heterogeneous and are influenced by sociodemographic factors like race and ethnicity, disease biology (laboratory markers, cytogenetics) and access to transplantation (Al-Hamadani, Hashmi, and Go 2014; Ailawadhi et al. 2016). Several large population-based studies report that Hispanics have low stem cell utilization rates, limited access to novel therapeutics and clinical trials as well (Ailawadhi et al. 2018; Costa et al. 2015; Schriber et al. 2017; Pulte et al. 2014). Hence, outcomes for Hispanics and AA lag behind non-Hispanic Whites as well (Pulte et al. 2014). We wanted to evaluate outcomes of MM patients at Montefiore Medical Center where AA and Hispanics have access to novel agents and therapeutics, and most of whom hail from a poor socio-economic status. Methods: We obtained a cohort of patients diagnosed with MM between 1/1/2000-12/31/2017 from the Montefiore Medical Center Cancer Registry database via Clinical Looking Glass software. Socio-demographic characteristics including self-reported ethnicity, date of diagnosis, histology, laboratory parameters (hemoglobin (Hgb), creatinine (Cr), albumin (Alb), serum lactate dehydrogenase (LDH)) within 30 days of diagnosis were obtained. Ethnicity and race variables were condensed to Hispanics, Non-Hispanic Whites (NHW) and Non-Hispanic African Americans (NHAA). Charlson comorbidity score and its age-adjusted version were calculated. Primary payor (Medicaid, Medicare, private insurance or self-pay) was identified for each patient. Descriptive statistical analysis was performed using STATA 15.1 statistical software. OS was estimated using the Kaplan-Meier method and HR and corresponding 95% confidence intervals (CI) were estimated using the cox proportional hazard model. All the variables in the Cox proportional hazard ratio model fulfill the proportional hazard assumption. Results: We identified 1630 patients during the study period; 1502 patients were available for analysis (Table 1) The mean age of diagnosis was 66 years, and NWH were diagnosed at older age when compared to Hispanics or NHAA (71 vs 64 vs 66, p=0.001) respectively. Hispanics had a higher proportion of Medicaid affiliation. The baseline mean Hb (p=0.02), Cr (p=0.02) and LDH (p=0.09) were different; however this difference is unlikely to be clinically relevant (Table 1). Median survival for the cohort was 63 months (95% CI: 59-69). Hispanics had better mean OS (118 months, (95% CI 96-128) as compared to NHW (49 months, 95% CI 40-68)) and NHAA (60 months, 95% CI 53-66) and others (32 months, 95% CI 21-46) (Figure 1). After controlling for age at diagnosis, gender, socioeconomic status, modified Charlson age score, race had a statistically significant impact on the outcome, with NHW (HR-2.01) and NHAA (HR 1.77) having poorer survival when compared to Hispanics (P

Description: Introduction Myeloma patients that experience a pathological fracture have 44% increased risk of mortality compared to their counterparts without pathological fractures. Given the negative impact of pathological fractures on survival, we have explored if access to obtain a therapeutic procedure influences the survival. We analyzed the nationwide inpatient cohort to evaluate for access to procedures and other hospitalization variables for myeloma patients admitted to the hospital for the diagnosis of pathologic fractures. Methodology Myeloma patients admitted in the hospital for the primary diagnosis of pathologic fractures from 2001-2010 were analyzed from the Nationwide Inpatient Sample (NIS). Procedures and diagnoses were identified using ICD-9-CM and NIS CCS codes. Variables of therapeutic procedures, length of stay (LOS), in-hospital mortality (IHM) and hospital charges were explored using multivariate logistic regression. Costs are derived from total hospital charges using cost-to-charge ratios based on hospital accounting reports from the Centers for Medicare and Medicaid Services and reflect the actual costs to produce hospital services. Results Of the 5154 myeloma patient admitted for pathological fractures, 2422 patients (47%) underwent a therapeutic procedure. The mean LOS for the primary diagnosis was 7.23 days (SE 0.14); cost for the hospitalization was $19344 and the IHM is 2.32%. The probability of getting a therapeutic surgical procedure and the cost of hospitalization is lower in patients 〉65, but had similar LOS and IHM compared to patients 65) and those that have the payer status of medicare and medicaid are significantly associated with the probability of not getting a therapeutic surgical procedure when they are admitted with pathological fracture. However, this did not result in increased in-hospital mortality suggesting that probably pathological fractures may reflect the biology of the underlying disease with negative impact on survival or the morbidity associated with a pathological fracture may impede the long term survival in myeloma patients. Disclosures: Lonial: Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Description: Background Myeloma patients have experienced great survival benefits in the last decade due to the use of novel agents and autologous stem cell transplant (ASCT). Prior studies report a complex interplay between payer status and the receipt of ASCT. We have evaluated if the payer status affects outcome metrics of length of stay (LOS), in-hospital mortality rate (IHM),  and total hospitalization charges in the context of survival benefit of myeloma with this procedure. Methods We used the NIS (Nationwide Inpatient Sample) 2001-2010 database (part of the HCUP database) to obtain the patient data.  Using private insurance as the reference group, we performed multivariate logistic regression to understand the association of payer status with LOS, IHM, hospitalization charges. We adjusted our model for age, race and the presence or absence of co-morbidities. Comorbidites were identified using comorbidity software that created measures reported by Elixhauser et al. Results From 01/2001 until 12/2010, 25656 admissions for ASCT as principal procedure for the principal diagnosis of multiple myeloma were included in our analysis. The IHM rate during this period based on payer status was 3.04%, 1.56%, 1.20% and 0.4% for medicare, medicaid, private insurance and others, respectively. Median LOS for medicaid and medicare were 17 days while private insurance and other insurances had a median LOS of 16 days. Medicare patients undergoing ASCT had higher likelihood of IHM compared to private insurance [Odds ratio: 2.62 ( 95%CI 1.46 – 4.72)]; while medicaid patients had non-significant increase. LOS in medicaid patients was longer compared to private insurance [(Odds ratio: 1.53 ( 95%CI 1.16-2.02)]. Conclusion  Myeloma patients with medicare undergoing ASCT had higher likelihood of in-hospital death compared to patients with private insurance. Medicaid patients had a lengthier in-hospital stay but there seems to be no significant difference in hospitalization charges in the different payer groups. However, the acceptable overall cumulative mortality rate suggests that myeloma patients can continue to enjoy the survival benefits associated with ASCT despite payer status. Further studies evaluating long-term outcomes outside the hospital admission would be required to better understand the association of payer status with overall survival benefits of ASCT. Disclosures: Kaufman: Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Boise:Onyx: Consultancy. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Description: SF3B1 mutations are the most frequently occurring splicing factor mutations in MDS and AML, however the misspliced genes that contribute the malignant state in SF3B mutant MDS or AML remains unclear. We determined that SF3B1 mutant cases of MDS express a longer, active isoform of interleukin 1 receptor associated kinase (IRAK4). IRAK4 is a serine/threonine kinase that is downstream of toll-like receptor (TLR) signaling and leads to activation of oncogenic signaling states, including NF-kB and MAPK. Examination of IRAK4 by RNA sequencing showed that normal cells predominantly express small IRAK4 isoforms resulting from exclusion of the part of exon 6. These isoforms are targeted for proteosomal degradation leading to diminished IRAK4 expression and activation in normal cells. In contrast, a large proportion of MDS/AML samples with SF3B1 mutation show increased expression of an IRAK4 isoform that retains full exon 6, encoding the full-length protein (IRAK4-Long). Consequently, we show that expression of mutant SF3B1-K700E in leukemic cells is associated with increased NF-kB activity, suggesting that mutations in SF3B1 instruct expression of IRAK4 RNA isoforms with maximal functional potential. Furthermore, SF3B1 mutant MDS and AML cells exhibited a block in hematopoietic differentiation in clonogenic assays. This differentiation block was ameliorated with pharmacologic inhibition of IRAK4 with CA-4948, a potent oral clinically useful small-molecule inhibitor of IRAK4. CA-4948 blocked TLR-stimulated cytokine release in various cell models and also led to decreased leukemic burden in mice xenografted with SF3B1 mutant MDS/AML cells. Finally, we determined that SF3B1 mutation induced IRAK4 activation led to TRAF6 mediated K63 ubiquitination of critical cell cycle and regulatory proteins directly implicated in oncogenesis. We had recently shown that U2AF1 mutations can lead to IRAK4 activation via retention of exon 4 (Smith et al, Nat Cell Bio, 2019). Our data now demonstrate that SF3B1 leads to overactivation of IRAK4 via retention of a different exon (exon 6), thus reinforcing that IRAK/TRAF6 activation is a common downstream oncogenic pathway in splicing factor mutated MDS/AML. Taken together, in this study, we find that mutations in SF3B1 induce expression of therapeutically targetable "active" IRAK4 isoforms and provide a genetic link between a spliceosome mutation and oncogenic innate immune signaling in MDS and AML. Disclosures Booher: Curis: Employment. Ramachandra:Aurigene: Employment. Samson:Curis: Employment. Will:Novartis Pharmaceuticals: Research Funding. Steidl:BayerHealthcare: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Consultancy; Stelexis Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Co-Founder; Pieries Pharmaceuticals: Consultancy; Aileron Therapeutics: Consultancy, Research Funding. Starczynowski:Kurome Therapeutics: Consultancy. Verma:Janssen: Research Funding; BMS: Research Funding; Celgene: Honoraria; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria.

Description: Introduction Adult T-cell leukemia/lymphoma (ATLL) is a rare, aggressive T cell neoplasm associated with a retrovirus human T cell lymphotropic virus (HTLV-1) and carries a dismal prognosis. Within the United States, New York, and Florida see the majority of cases due to the concentration of Caribbean immigrants (Zell, Assal et al. 2016, Malpica, Pimentel et al. 2018). SEER data does not include states like New York and Florida where most cases are seen and therefore a true estimate of the disease burden in this country is not known (Chihara, Ito et al. 2012, Adams, Newcomb et al. 2016). Aim We aim to study the epidemiology and clinical outcomes of ATLL in the United States particularly in the state of New York. Methods Data for New York was obtained from the New York State Cancer Registry (NYSCR). Data were also retrieved from 18 Surveillance, Epidemiology, and End Results (SEER) registries in the United States. Patients with ATLL (HTLV-1 positive) (includes all variants) were categorized using the International Classification of Diseases for Oncology, Third Edition codes ICD-O-3 as 9827/3. Race/ethnicity was categorized as non-Hispanic white, non-Hispanic black, all Hispanic and other/unknown in the NYSCR whereas it was categorized as non-Hispanic white, non-Hispanic black, all Hispanic, non-Hispanic American Indian/Alaska Native, non-Hispanic Asian or Pacific Islander, and non-Hispanic unknown race in SEER. ATLL patients ≥ 15 years of age were identified from 1995 to 2014 in SEER and all ages were included in NYSCR. Survival was estimated from SEER follow-up data with Kaplan Meier survival analysis. For NYSCR mean and median survival time (month) for deceased patients - cases diagnosed through death certificate only were removed. NYSCR does not conduct active patient follow-up and assumes patients are still alive if we didn't find a deathmatch through vital record or National Death Index linkages. Results Five hundred and eleven patients with ATLL were identified in SEER. These patients had a median survival of 8 months (m) which was worse than all other subtypes of peripheral T cell lymphoma. (Figure 1) Four hundred and twenty-nine patients with ATLL were identified in NYSCR and these patients had a median survival of 4.5 m. (Figure 2) Over the years from 2000 until 2014 the number of cases diagnosed within SEER registry coverage areas has not changed. In New York state however there has been a doubling in the number of cases diagnosed from 1995 to 2014. (Figure 3A, B) The non-Hispanic black population was diagnosed at a median age of 52.5 in SEER and 54 in NYSCR while the non-Hispanic whites were diagnosed at a median age of 71 in SEER and 64.5 in NYSCR. The Hispanic patients were diagnosed at a median age of 58.5 in NYSCR and 52.5 in SEER. (Figure 4A, B) There was no gender predominance with 50% males in both registries. ATLL patients in SEER were 47.2% non-Hispanic white, 31.7% non-Hispanic black, 9.8% Hispanic and 11.4% other/unknown. There were 5.5% Japanese patients (n=28) diagnosed in SEER. NYSCR had 22.4% non-Hispanic white, 59.4% non-Hispanic black, 15.9% Hispanic and 2.3% other/unknown. (Figure 5A, B) Within SEER registries most cases occurred in New Jersey, California, Connecticut and Georgia. (Figure 6) New York state had a significantly higher number of cases than these states. Seventy four percent cases diagnosed within New York state are diagnosed in New York city and only 26% of cases are diagnosed in upstate New York. Based on reported country of birth within New York state, only 27% of the ATLL cases diagnosed are born in the US whereas 49% are born in the Caribbean (most likely to be from Jamaica, Dominican Republic and Haiti). (Figure 7A, B, C) For SEER and NYSCR the age-adjusted cancer incidence rate by race year and other factors will be presented at the meeting. Conclusions ATLL has a worse prognosis than all other PTCL subtypes. New York State has a high endemicity for ATLL with a rising number of cases. The higher percentage of non-Hispanic black patients in New York compared to the rest of the country is consistent with the diverse racial demographics in this state. Survival varied significantly by race/ethnicity and disparities were evident especially for non-Hispanic blacks who were diagnosed at a younger median age and had a shorter survival. Further research into this aggressive disease is needed to improve outcomes for these patients. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: As people with HIV live longer, the epidemiology of plasma cell disorders (PCD) including MGUS, smoldering myeloma and Multiple myeloma (MM) becomes relevant and remains unknown. Moreover, patients with HIV have a higher incidence of monoclonal proteins which may not be related to an underlying lymphoproliferative disorder[1, 2] . There are mostly anecdotal reports and very few studies in HIV myeloma[3]. A retrospective study of 10 patients with HIV+ve symptomatic MM reported possible therapeutic benefit of ART and reported better overall survival of HIV+ve MM on ART as compared to HIV -ve MM. There is a paucity of data in PCD in this population whose incidence can be expected to increase globally. We conducted a single-institution retrospective study to look at the incidence of PCD. Methodology:We reviewed an electronic database of patients with HIV related PCD treated at Montefiore Medical Center between 2001 and 2018. All patients with a new diagnosis of PCD between January 1 2001 to July 15 2018 were identified. Data on patient demographics, HIV status, clinical outcomes (including mortality) and therapy was collected. Results: Between 2001 and 2018, 14438 patients were identified with HIV and 1986 patients had a monoclonal band in SPEP (13.8%). Based on our previous study, patients who had a definitive monoclonal band or suspected MM underwent a BM biopsy. 34 patients were diagnosed with PCD --MGUS 16 (47.05%), Smoldering MM 1 (2.94%), MM 16 (47.05%) and Primary plasma cell leukemia (PCL) 1 (2.94%). The majority of the patients were AA consistent with demographics of the Bronx. Interestingly HCV co-infection was identified in 50% (n=17) of patients and HBV co-infection was present in 15% (n=5) patients. The median CD4 count was 381 (12-1080), median viral load 237 (0-501534) and 53% patients were on ART at the time of diagnosis. The median time from HIV diagnosis was 13.9 (-2.8 to 29) years. In patients with MGUS the predominant heavy chain involvement was IgG, the median protein on SPEP was 1.1 g (0.7-1.9 g) and percentage of BM involvement was 5% (2-10%). In patients with MM IgG was the predominant heavy chain involved. On presentation, ISS Stage was Stage I in 2 patients (15.4%), 4 (30.7%) had at least Stage 2, 7 patients (53.9%) had stage 3. On presentation, 10 (58.8%) patients presented with anemia, 10 (58.8%) presented with renal impairment (Cr〉=1.3), 16 (94.1%) presented with bone lesions, 6 (37.5%) presented with hypercalcemia. 5 patients (34.6%) had extramedullary presentation including 1 patient (2.9%) with PCL, 2 (5.8%) with anaplastic plasmacytoma. All patients were treated with an imid or bortezomib based regimen and there were no unusual side effects in these patients. 5 patients (29.4%) underwent autologous stem cell transplant with successful outcomes. Discussion: The prevalence of a positive SPEP is 13.8% in patients with HIV and the prevalence of plasma cell dyscrasias (PCD) in our population is 0.02%. A previous study from this cohort[2] showed that approximately 6.4% of patients with a positive SPEP developed hematological malignancy and all patients with a faint monoclonal band had lymphoma (70.5%) and those with a definite monoclonal band had myeloma (29.5%). Even though prevalence is less than the general population rate of 3%, as patients with HIV live longer this number may increase. In our study there was a high rate of co-infection with HCV in patients who had a PCD and this needs further investigation to determine causality. PCD developed at a median of 13.9 years after HIV diagnosis. The ISS staging distribution in patients presenting with myeloma is consistent with non HIV myeloma. People with HIV tolerate standard imid or proteasome inhibitor based triple drug therapy and have successful outcomes with autologous transplantation. This is the largest cohort and report describing PCD in HIV population. References:Jou, E., et al., Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies. Ann Hematol, 2016. 95(4): p. 575-80.Jou, E., et al., Retrospective study of the prevalence and progression of monoclonal gammopathy in HIV positive versus HIV negative patients. Hematol Oncol, 2017. 35(1): p. 64-68.Li, G., et al., A retrospective analysis of ten symptomatic multiple myeloma patients with HIV infection: A potential therapeutic effect of HAART in multiple myeloma. Leukemia Research, 2014. 38(9): p. 1079-1084. Disclosures Janakiram: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: World Health Organization (WHO) classifies therapy-related myeloid neoplasms (t-MN) into therapy related acute myeloid leukemia (t-AML), therapy related myelodysplastic syndrome (t-MDS), and therapy related myelodysplastic syndrome/myeloproliferative neoplasms (t-MDS/MPN). These diseases are aggressive hematological malignancies and only allogeneic transplant offers the possibility of long-term remission. We performed retrospective analyses of Surveillance, Epidemiology, and End-Results (SEER) database to examine differences in incidence and survival outcomes of t-MN across different races and ethnicities in United States (US). Methods: Patients who developed t-MN following previous hematological or solid organ malignancies were included in the analyses. SEER registries classify race, ethnicity using 2000 US Census categories based on self- identification, medical records, death certificates and though linkage to Indian Health Service records. The race/ethnicity was categorized as non-Hispanic white (nHW), Hispanic white (HW), non-Hispanic Black (nHB), non-Hispanic Asian/Pacific islander (nHA/P), non- Hispanic American Indian/ Alaskan natives (nHI/A) and unknown groups (U). The patients were divided into various age group categories: 80 years. The statistical analyses were performed using SAS 9.4 software. Results: 13990 patients were reported to SEER database during 2000-2012 period with the diagnosis of t-MN. The total number of newly diagnosed t-MN in various racial groups was: nHW-11307, HW-900, nHB-1018, nHA/P-708, nHI/A -51 and U-6. There was higher reporting of non-Hodgkin lymphoma in females and lung/bronchial malignancies in males across all racial groups. Comparing different age groups, 50 months OS rates were: 2%, 6%, 13%,22% and 26% for groups 〉80 years, 70-79 years, 60-69 years, 50-59 years and

Description: Introduction A recent Spanish study suggested an impact of the type of hospital (teaching versus non-teaching) on survival of multiple myeloma (MM) patients. Such data, as well as other hospitalization parameters such as indications, length of stay (LOS), in-hospital mortality (IHM)  in MM patients admitted to hospitals in the U.S are lacking. We have explored the National Inpatient sample (NIS) data to address the indications for hospitalization in MM patients and their survival outcomes of the hospitalization. Methods We obtained the National Inpatient Sample (NIS) data for the years 01/2001 until 12/2010 from Healthcare Cost and Utilization Project database (HCUP) database. The 2010 NIS contains all discharge data located in 45 States, approximating a 20% stratified sample of the U.S hospitals. Teaching hospital was defined as a hospital supported by AMA-approved residency program, is a member of the council of teaching hospitals or has a ratio of full-time equivalent interns and residents to beds of ≥0.25. Results A total of 178354 admissions reported to NIS were analyzed. Majority of admissions were to teaching hospitals (61.7% admissions: 45.8% for non-SCT and 15.9% for SCT indications) (Table 1). Among the patients that were admitted for non-SCT indications, significantly younger patients were admitted to teaching hospitals. Complicated procedures such as cancer chemotherapy were admitted to teaching hospitals (teaching vs. non-teaching: 8.3% vs. 3.4%; p=