ALBERT

Description: Background The ability of a person with hemophilia to adhere to treatment recommendations aimed at preventing and controlling bleeding likely impacts clinical outcomes and resource utilization. Annual cost of replacement factor for persons with severe hemophilia on prophylaxis is estimated to be as high as $300,000 per year (Johnson KA and Zhou ZY. ASH Annual Meeting Educational Program. 2011; 413-418). Hemophilia care is optimized when delivered by a highly specialized hemophilia treatment center (HTC) (Soucie et al. Blood. 2000; 96: 437-442). Consolidation of care for persons with hemophilia from a large geographic region within an HTC results in demographic heterogeneity that may impact an individual's ability to adhere to treatment recommendations. Little is known regarding the impact of socio-demographic factors on treatment outcomes for persons with hemophilia. The purpose of this study was to identify disease-related, treatment-related and demographic variables that have a significant impact on morbidity and resource utilization. Methods We identified 69 persons with severe hemophilia treated at our HTC between June 2009 and June 2012. We collected data for the variables listed below in table 1. To assess morbidity and resource utilization, we collected data for total factor use, total outpatient cost, total inpatient cost, frequency of inpatient and outpatient encounters and length of stay when hospitalized. Risk factors were identified using linear regression. A subset analysis was performed to evaluate the impact of prophylaxis on patients without inhibitors. All statistical analyses were performed using STATA (version 12.0 College Station, TX). Statistical significance was defined as P 〈 0.05. Results Age and inhibitor status were the only variables to significantly impact cost in both inpatient and outpatient settings (Table 1). The statistically significant beneficial impact of prophylaxis was confirmed by subgroup analysis of patients without inhibitors with respect to number of hospitalizations and length of stay, but not total cost. Conclusions Identifying and addressing potential barriers to care will likely reduce morbidity and cost for persons with hemophilia. Caregiver status and age are demographic variables that may contribute to poor medical adherence resulting in increased morbidity and cost of care for persons with severe hemophilia. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction The United States Thrombotic Microangiopathy (USTMA) Consortium consists of high-volume US referral centers that are committed to collaborative research in TMAs. The USTMA Immune Thrombotic Thrombocytopenic Purpura (iTTP) registry has compiled retrospective data on demographics, treatments and outcomes in patients with iTTP to create the world's largest database of patients with this rare disease. While there is consensus on the use of therapeutic plasma exchange (TPE) for treatment of iTTP, there are no large randomized trials on which to base use of rituximab. The drug is frequently used for refractory or relapsed iTTP, but is currently being used more frequently for de novo (first episode) iTTP. We queried the USTMA iTTP registry to determine whether relapse free survival (RFS) is superior when rituximab is added to TPE and corticosteroids for treatment of iTTP. We hypothesized that the addition of rituximab would improve RFS at 5 years in both de novo and relapsing iTTP. Methods Following IRB approval at each institution, investigators independently reviewed individual patient records to confirm diagnostic criteria and entered demographic, treatment and outcomes data into the REDCap database housed at the University of North Carolina. The diagnosis of iTTP was defined as ADAMTS13 〈 10% or ADAMTS13 〈 20% with an inhibitor or antibody detected at any point or a clinical diagnosis of iTTP based on presenting characteristics, response to treatment and/or relapsing phenotype before ADAMTS13 testing became available (N=173). Relapse was defined as a recurrence of iTTP after at least 30 days of remission (recurrence within 30 days was considered an exacerbation, or continuation of the prior episode). To explore the effect of rituximab added to TPE and corticosteroids, we first assessed the treatment effect in de novo iTTP patients and then separately in relapse. We constructed Kaplan-Meier curves to compare RFS for patients treated with rituximab plus corticosteroids versus corticosteroids alone in both groups, and compared RFS at specific time points using the Klein method. To better understand whether other patient variables had an effect on RFS in both de novo episodes and relapses, ordinary (time-to-event) and mixed-effects (recurrent time-to-event) Cox proportional hazards models were used to examine the relationships of treatment, race/ethnicity, sex, age, treatment year, and presenting signs/symptoms with the outcome. Analyses were conducted using R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). Results As of July, 2019, the USTMA database contains 775 unique study patients with a confirmed diagnosis of iTTP with 1397 unique iTTP episodes. The treatment of patients' de novo iTTP episode was available for analysis in 375 patients, 188 of whom were treated with corticosteroids alone, 131 with corticosteroids plus rituximab, and 56 with other therapies. RFS was significantly higher in patients treated with corticosteroids and rituximab compared to those treated with corticosteroids alone at 1 year (0.93 vs. 0.78, p=0.0002) and 3 years (0.82 vs. 0.66, p=0.004) but not 5 years (0.60 vs. 0.56, p=0.39). In addition, the risk of relapse decreased with later treatment year for de novo iTTP (hazard ratio (HR) 0.95, 95% CI 0.92-0.99, p=0.03), consistent with rituximab use increasing over time, and was increased in African Americans compared with Caucasians (HR 1.83, 1.10-3.06, p=0.02). We then explored the treatment effect in all iTTP relapses (743 relapses in 426 patients). Here, a significant (p=0.0007) interaction between treatment and race was found. Among African Americans, we found no difference in RFS when rituximab was added (HR 1.15, 0.81-1.62, p=0.43). However, among Caucasians, RFS was significantly improved when rituximab was added (HR 0.15, 0.06-0.35, p

Description: Abstract 4126 HIV-infected patients have a significantly longer life expectancy in the era of HAART, but also have an increasing incidence of malignancies. A 2.5-fold increase in leukemia (Patel et. Al., Annals of Int Med. 2008, 148:728-736) has been documented in HIV-infected individuals, including a two-fold increase in AML incidence, with a predominance of M2 and M4 subtypes (Aboulafia et. al., AIDS 2002, 16:865-876 and Sutton et. al., Br J Hematol 2001,112:900-908). To further characterize the biology and outcome of AML in HIV-infected patients in the HAART era, we reviewed the experience with these patients at the University of Maryland Greenebaum Cancer Center and the Johns Hopkins Kimmel Cancer Center. All patients were from greater Baltimore, a city with 37.7 new HIV cases per 100,000 population, the second highest among U.S. cities (Baltimore City HIV/AIDS Statistics Fact Sheet, April 18, 2008. Department of Health and Mental Hygiene, State of Maryland). After IRB approval was obtained, cases were identified by review of all AML patients seen at both institutions between 2002 and 2009. Data regarding patient age, gender, white blood cell count, AML subtype, karyotype, FLT3 mutation analysis, HIV treatment, CD4 count, HIV viral load, AML treatment and treatment outcome were collected. We report 8 HIV-positive AML patients diagnosed and treated in Baltimore, Maryland in the HAART era. Six patients had M2 or M4 subtype (four M2, two M4, one M1 and one M5). One M2 patient had t(8:21) and one M4 patient had inv(16); other abnormalities included del(7p) in one M4 patient, a complex karyotype in two M2 patients, one of whom had treatment-related AML. Three patients had a normal karyotype. FLT3 was wild-type in six patients, and was not studied in two. All but one patient had CD4 counts below 200 cells/μL. HAART was incorporated into the treatment of seven of our eight patients. Multiple HAART regimens were used, and treatment was variable. One patient received HAART during induction, but not consolidation. The other seven patients started or resumed HAART at some point during consolidation. AML was not treated in one patient who had rapidly progressive multiorgan failure at AML presentation. Seven patients were treated with standard induction chemotherapy; six achieved complete remission (CR), while one had refractrory disease. All six patients received consolidation with high-dose cytarabine. Complications during consolidation therapy included prolonged neutropenia in three patients, subdural hematoma secondary to prolonged, severe thrombocytopenia in one patient, and cerebellar toxicity in one patient. Disease-free survival (DFS) ranged from 15 weeks to 20 months, with a median of 10 months. One patient developed diffuse large B-cell lymphoma following completion of consolidation therapy. CD4 count, viral load and treatment of HIV did not correlate with ability to tolerate consolidation, nor with DFS. We conclude that HIV-infected AML patients achieve CR, but have poor tolerance of consolidation therapy and short DFS. Based on our data and the literature to date, CBF abnormalities may occur at an increased rate in these patients, but are not associated with favorable outcomes. Further investigation is needed to substantiate a relationship between HIV and CBF mutations, and to develop treatment strategies for AML therapy, HAART and supportive care to improve outcomes. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1432 TMAs occur frequently in association with HIV, although the exact mechanism leading to hemolysis is unclear (Crum-Cianflone NF, Weekes J, and Bavaro M., AIDS Patient Care and STDs. 2008, 22:771-778.) Thrombotic microangiopathies comprise a spectrum of diseases including thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS). The role of HIV infection in the development of TTP has been a topic of some controversy. Overlap between TTP and HIV associated pathological entities, including malignancy and malignant hypertension, may complicate the clinical presentation (Benjamin et al., CID. 2009, 48: 1129–1136). However, patients meeting a clinical diagnosis of TTP are treated successfully with plasma infusion therapy (Novitzky et al., B J Haematol. 2005, 128:373-379) suggesting a molecular process resulting in the depletion of plasma components. Such processes would include TTP/HUS and defects in complement regulation, but not disseminated malignancy or malignant hypertension. To further characterize the biology and outcome of TMA in HIV-infected patients, we reviewed the experience with these patients at the University of Maryland Greenebaum Cancer Center. All patients were from greater Baltimore, a city with 37.7 new HIV cases per 100,000 population, the second highest among U.S. cities (Baltimore City HIV/AIDS Statistics Fact Sheet, April 18, 2008. Department of Health and Mental Hygiene, State of Maryland). After obtaining IRB approval, we identified cases by review of all TMA patients treated by our plasma exchange service between 2000 and 2008. Twenty-one episodes of TMA occurred in twenty patients with HIV. One patient had had a prior episode of TMA, one in 1995 preceding our review, and one with multiple episodes in 2002 and then again in 2008. The median age of our patients was 43 years, all were African American, seven were men and fourteen were women. Seven patients were also infected with hepatitis C, one with hepatitis B, and two with both hepatitis B and C. Median CD4 cell count for all patients was 70 × 106 cell/L. Twelve patients were on or previously prescribed antiretroviral medications and eight patients were not. There was no significant difference in CD4 counts between these groups. Three patients were diagnosed with HIV at the time of TTP presentation. Median duration of HIV infection prior to presenting with TMA was 7 years. Median LDH was 3301 units/L with all but two patients having a value greater than 1000 units/L. One of these patients had an LDH of 507 units/L. The other patient (LDH 274 units/L) had a history of TTP 6 years prior that responded to plasma exchange. Neurologic abnormalities were found in nine patients (excluding dizziness) and diminished renal function (Cr 〉 1.5 mg/dL) was noted in fourteen patients. ADAMTS13 levels were not measured. The median number of plasma exchanges was 13, with seven patients requiring more than 20 treatments. Four patients were treated with rituximab following failure of plasma exchange. Five patients died. Among these patients HIV viral load was variable ranging from undetectable to 〉750,000 copies, however four patients had CD4 cell counts 〈 50 × 106 cells/L. All but one patient with CD4 cell counts ≥ 50 × 106 cells/L responded to plasma exchange. Two patients with CD4 counts below 10 × 106 cells/L responded to plasma exchange. Of the patients treated with rituximab, two patients had a prompt, favorable response and two ultimately died (Evans et al., AIDS Patient Care and STDs, 2010, 24: 349-52). One of the patients who died had a CD4 count of 2 at the time of rituximab treatment. The other patient had a history of previous TMA in 2002 that eventually responded to 32 plasma exchange treatments. In 2008, she again presented with TMA with thrombocytopenia, and was treated with 19 plasma exchanges prior to receiving rituximab. Her CD4 count at that time was 138 × 106 cells/L. She did respond promptly to rituximab, but developed further thrombocytopenia 2 months later. On this final presentation she was diagnosed with lymphoma, to which she ultimately succumbed. HIV-associated TMA meeting clinical criteria for TTP is generally responsive to standard treatment with plasma exchange, however alternative diagnoses must be excluded. Rituximab may be effective in carefully chosen patients failing plasma exchange. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Thalassemias are common inherited hematologic disorders worldwide, and with increasing migration, its prevalence evolves in different countries. However, community prevalence across most of the United States is unknown. Minnesota, particularly Minneapolis/St. Paul, has a relatively large community of immigrant families, with focal ethnic clusters of Karen and Hmong individuals from Southeast Asia, Liberia, and neighboring countries in Western Sub-Saharan Africa. Statewide data show that these ethnic minority populations have grown in the past decade; it is unknown whether thalassemia prevalence mirrors these migration trends. This report aims to quantify the demography and disease characteristics of children with thalassemia mutations seen at University of Minnesota/M Health Fairview (MHF) diagnosed between January 1, 2010 and December 31, 2019. Methods An institutional review board-approved electronic medical record (EMR) review was undertaken. Patients born on or after January 1, 2001 were included if they received medical care within the MHF system and thalassemia status could be confirmed. The prevalence by thalassemia type, demography, language, treatment details, and specialist involvement were detailed. A patient's ethnicity determination was defaulted to "American" if the ethnicity and/or immigration country of origin going back at least two generations could not be confirmed via EMR. The trends of new diagnoses over the decade were reviewed and compared to available state demography data trends. Descriptive statistical analyses were performed for the full group and by thalassemia type. Results A total of 404 patients met inclusion criteria, representing 48 country or region-specific ethnicities, 17 known countries of birth, and 30 separate languages. The most prevalent immigrant ethnicities were Karen (15%), Hmong (10%), and Vietnamese (5%), representing the 14th, 2nd, and 6th-largest immigrant communities in the state, respectively (www.mncompass.org). In Minnesota, the Asian population grew by 32% (69,800 people) between 2010-2018 (Minnesota State Demographic Center, https://mn.gov/admin/demography/data-by-topic/age-race-ethnicity/). The overall number of thalassemia diagnoses also increased over the decade, with Karen patients representing the largest proportional increase over the available time frame (Figure 1). Including both trait and disease, alpha thalassemias were more frequently diagnosed than beta thalassemias (63% versus 37%). Of the alpha thalassemias, 79% were suspected or confirmed 1-2 gene deletions based on newborn screening. Eleven (2.7%) had hemoglobin (Hb) H disease and 2 (0.5%) had alpha thalassemia major. Beta thalassemia intermedia, beta thalassemia major, and HbE were collectively 5.4% of all patients, 59% of whom were transfusion-dependent. Genetic confirmation was performed for 10.4% of all thalassemias. Those with alpha thalassemias were more ethnically diverse. Aside from those categorized as "American", those with beta thalassemias were more likely to be Karen (25%), while those with alpha thalassemias were most likely to be Hmong (14.4%). Seven had chelation prescribed during the time frame and 5 underwent bone marrow transplant. Only 16% were seen by a hematologist in the MHF system, though the yearly trends of hematology care did not match the increased diagnostic rate (Figure 2). Conclusions The incidence of pediatric thalassemia diagnoses have increased over the past decade at MHF, somewhat reflecting the statewide demographic trends. However, most patients are never being seen by hematology. A caveat to the data described is the fact that MHF is 1 of 2 pediatric hospitals locally, with the other having the historically larger thalassemia patient population. Thus, while these data offer crucial insights into the potential frequency of thalassemia mutations in our state, they also are likely to significantly under-represent the local prevalence. Also, the data do not reflect the prevalence in youths diagnosed prior to 2010 or the adult prevalence, for which institutional investigations are currently ongoing. These data illuminate the need to ensure adequate educational resources and financial support for these primarily non-English-speaking communities to improve awareness for families and medical providers and offset substantial medical costs for life-saving therapies. Disclosures No relevant conflicts of interest to declare.