Cost and Efficacy of Upfront Plerixafor Versus a “Just-in-Time” (JIT) Approach in Hematopoietic Progenitor Cell (HPC) Mobilization

Abstract HPC mobilization with plerixafor (Plex) plus G-CSF (G+P) results in superior CD34+ cell yield, when compared to mobilization with G-CSF alone in patients with myeloma and lymphoid malignancies. However, Plex-based approaches are associated with high mobilization costs. To circumvent higher costs, several institutions use a so-called JIT approach, where Plex is only administered to patients likely to fail mobilization with G-CSF alone. Whether such a JIT-Plex approach is cost effective has not been confirmed to date. We present here, a single institution comparative analysis of 137 patients with myeloma and lymphoma who underwent mobilization with 2 different approaches of Plex utilization. Between Jan 2010-Oct 2012 (n=77) patients received mobilization G-CSF (10 μg/kg) for 5 days and Plex (0.24 mg/kg) on the evening of day four, 11 hours before apheresis the following day (G+P). To reduce mobilization costs between Nov 2012-Jun 2014 (n=60) patients were mobilized with JIT-Plex where Plex was only administered to patients likely to fail mobilization with G-CSF alone (i.e. patients with a day 4 peripheral blood (PB) CD34+ count of <10/μL, or those with day 1 yield of < 1.0 X 106 cells/kg or day 1+2 yield of <1.5 X 106 cells/kg ABW. Mobilization failure was defined as inability to collect at least 2 X 106 /kg CD 34+ cells. Patients in G+P had a higher mean peak PB CD34+ cell count (77 vs. 33.1 cells/μL, p<0.001) and a higher mean CD34+ cell yield on day 1 of collection (4.4 X 106 vs. 2.4 X 106 cells/kg ABW, p=0.0005). The mean total CD34+ cell collection was also higher in G+P (6.64 X 106 vs. 4.81 X 106 cells/kg ABW, p=0.0068). In the JIT-Plex group 41% (n=24) completed adequate HPC collection without Plex. Mobilization failure was noted in 5 patients in the G+P group (3 were salvaged with bone marrow harvest) and 2 patients in the JIT-Plex group. Two patients in either group did not proceed to AHCT as a result of mobilization failure. The mean Plex doses utilized in JIT-Plex was lower (1.3 vs. 2.1, p=0.0002), however 21% (n=16) in the G+P group completed apheresis on day 1 compared to only 6.9% (n=4) in JIT-Plex, p=0.0094. Cost analysis was estimated based on actual sales price (actual wholesale price AWP – (AWP X 0.2)) for mobilization agents and the United states (US) Department of Health and Human Services Centers for Medicaid Services (HHS/CMS) reimbursement rates for procedural costs associated with mobilization, apheresis or cryopreservation. The mean estimated cost was higher in the G+P group ($28,448 vs. $24,852, p=0.0315). Our analyses, for the first time confirms that mobilization with JIT-Plex allows for a safe, adequate and cost efficient strategy for HPC collection. Baseline Patent Characteristics at Time of Mobilization Table Mobilization Strategy Upfront Plerixafor + G-CSF (n=77) G-CSF + Just-in-time Plerixafor (n=60) p-value Disease Myeloma Lymphoma 46 (60%) 31 (40%) 30 (50%) 30 (50%) 0.29 Mean age, years (range) 58 (23-75) 57 (22-75) 0.45 Male gender 42 (55%) 33 (57%) 0.92 Race: Caucasian 73 (97%) 57 (98%) 1.0 Lines of prior therapy, mean 1.5 1.8 0.3 Prior Radiation 13 (18%) 12 (21%) 0.66 Mean KPS (range) 80 (70-100) 80 (60-100) 0.75 HCT-CI Score (mean) 2 2 0.36 Abbreviations: G-CSF-granulocyte-colony stimulating factor (filgrastim); KPS-Karnofsky performance status; HCT-CI- hematopoietic cell transplantation-specific comorbidity index Disclosures No relevant conflicts of interest to declare.

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Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for HCT Outcomes At US Transplant Centers: A Center for International Blood and Marrow Transplant Research (CIBMTR) Study

Blood ◽

10.1182/blood.v120.21.733.733 ◽

2012 ◽

Vol 120 (21) ◽

pp. 733-733 ◽

Cited By ~ 3

Author(s):

Mohamed L. Sorror ◽

Brent R. Logan ◽

Xiaochun Zhu ◽

J. Douglas Rizzo ◽

Kenneth R. Cooke ◽

...

Keyword(s):

Predictive Power ◽

Hematopoietic Cell Transplantation ◽

Mononuclear Cells ◽

Conflicts Of Interest ◽

Karnofsky Performance Status ◽

P Value ◽

High Dose ◽

Kappa Statistics ◽

Allogeneic Hct ◽

Significant Difference

Abstract Abstract 733 In 2005, the HCT-CI was introduced by a single institution as a weighted scoring system to predict mortality risk following allogeneic HCT. Since then, not all investigators were able to validate the HCT-CI after testing in their respective institutions. In 2007, a new prospective multi-institutional observational study was initiated at the CIBMTR to collect comorbidities from all transplant centers by their respective evaluators and to validate the predictive power of the HCT-CI in a large sample of patients (pts). The HCT-CI was adapted into the Pre-Transplant Essential Data (pre-TED) collection form #2400. Data managers from all institutions attended an education session on comorbidity coding per the HCT-CI at the 2007 Tandem BMT Meeting in Keystone, Colarodo. This session was then made public to all data managers at the CIBMTR website. <>The study accrued 8115 consecutive pts treated with allogeneic HCT from 12/2007 to 12/2009 from related (47%) or unrelated (53%) donors. Median age was 52 [range 1–78) years. Conditioning regimens were high-dose (67%) or either reduced-intensity (RIC) or nonmyeloablative (NST) regimens (34%). Diagnoses were acute (54%) or chronic (12%) leukemia, myelodysplastic syndromes (16%), lymphomas (16%), and others (2%). GVHD prophylaxis regimens were cyclosporine-based (22%), tacrolimus-based (68%), or others (10%). Stem cell source was marrow (17%) or peripheral blood mononuclear cells (83%). Karnofsky performance status scores were <90% (33%), ≥ 90% (62%), or missing (5%). HCT-CI scores were 0 (47%), 1 (15%), 2 (11%), 3 (12%), 4 (7%), 5 (3%), ≥6 (4%), or missing (1%). About 11% of pts with score 0 had other comorbidities listed. Overall, pts experienced cumulative incidence of transplant-related mortality (TRM) of 28% and a survival rate of 48% at 3-years. Pts with HCT-CI scores of 0 vs. 1–2 vs. ≥3 had 3-year TRM incidences of 24%, 28%, and 35% (p <0.001) and 3-year overall survival (OS) rates of 54%, 47%, and 38%, respectively (p <0.001, Figure). Proportional hazards models were used to estimate the hazard ratio (HR) for TRM and OS associated with HCT-CI scores. The models were adjusted for all previously mentioned covariates in addition to disease status, CMV serology status, gender, and race. Increasing HCT-CI scores (1–2 and ≥3 vs. 0) were associated with increases in the HR [95% confidence interval (CI)] for TRM [1.12 (1.00–1.26) and 1.47 (1.31–1.65), respectively, p<0.0001] and OS [1.12 (1.03–1.22) and 1.36 (1.25–1.48), respectively, p<0.0001] in the overall pt population. No statistically significant difference could be detected between pts with score 0 + other comorbidities vs. score 0 for TRM (HR 0.93, p= 0.385) or OS (HR 0.96, p= 0.474). When the HCT-CI was modeled as scores of 0, 1, 2, 3, 4, and ≥5 the HR for TRM were 1.00 vs. 1.12 vs. 1.13 vs. 1.31 vs. 1.52 vs. 1.77, respectively (, p<0.0001) and for OS were 1.00 vs. 1.13 vs. 1.12 vs. 1.22 vs. 1.39 vs. 1.62 (p<0.0001). Likewise, the HCT-CI could discriminate outcomes well among pts given high-dose or RIC/NST regimens and those diagnosed with lymphoid or myeloid diseases (Table 1). The inter-rater reliability (IRR) rate among data managers versus their respective investigators was assessed in 3 institutions. Weighted kappa statistics were 0.54, 0.81, and 0.47 respectively, indicating fair-moderate agreement rate among evaluators. The HCT-CI is a valid tool to discriminate relative risks for TRM and OS after HCT across different institutions, different conditioning intensities, and different diagnoses. The HCT-CI should be used as a standard-of-care health measure in counseling pts for HCT, in clinical trial design, and in adjusting statistical analyses for HCT outcomes. Future efforts will focus on improving the IRR of the HCT-CI. Table 1: Multivariate analyses TRM OS HCT-CI scores HR p-value HR p-value High-dose regimens 0 1.00 <0.0001 1.00 <0.0001 1 1.19 1.14 2 1.12 1.10 3 1.34 1.19 4 1.53 1.41 5+ 1.88 1.64 RIC/NST regimens 0 1.00 0.001 1.00 <0.0001 1 0.95 1.12 2 1.10 1.12 3 1.27 1.27 4 1.46 1.39 5+ 1.66 1.65 Lymphoid diseases 0 1.00 <0.0001 1.00 <0.0001 1 1.16 1.15 2 1.24 1.12 3 1.37 1.32 4 2.13 1.67 5+ 2.15 1.88 Myeloid diseases 0 1.00 <0.0001 1.00 <0.0001 1 1.12 1.13 2 1.00 1.06 3 1.25 1.14 4 1.29 1.27 5+ 1.63 1.52 Figure: 3-year OS as stratified by HCT-CI scores of 0 vs. 1–2 vs. ≥3 Figure:. 3-year OS as stratified by HCT-CI scores of 0 vs. 1–2 vs. ≥3 Disclosures: No relevant conflicts of interest to declare.

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Hodgkin Lymphoma Outcomes: Can We Expect Ethnic Parity in a Hispanic Prevalent Population?

Blood ◽

10.1182/blood-2019-129058 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4056-4056

Author(s):

Michelle Janania Martinez ◽

Prathibha Surapaneni ◽

Juan F Garza ◽

Tyler W Snedden ◽

Snegha Ananth ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Conflicts Of Interest ◽

Relative Survival ◽

Complete Response ◽

Statistical Testing ◽

P Value ◽

Hispanic Population ◽

Significant Difference ◽

The Mean

BACKGROUND It is estimated that 8110 persons will be diagnosed with Hodgkin Lymphoma (HL) in the US during 2019, but the advent of new treatment options has increased the cure rate to at least 80%. It has been reported that the rates of HL are lower in the adolescent and young adult (AYA) Hispanic population but significantly higher in the Hispanic population older than 65. The relative survival estimates are stated to be similar between AYA Hispanics (HI) and non-Hispanics (NH) but for ages 65-84, HI have a significantly higher mortality rate. Pediatric studies have suggested that ethnicity plays a role in outcomes in patients with HL but there is limited data in the adult population. There is an unmet need in the field, where dossiers on underrepresented ethnic minorities need to be carefully considered and compared to existing data. Therefore, our study aims to compare survival outcomes in Hispanics vs Non-Hispanics with HL, who were treated at the only NCI designated cancer center of South Texas. To our knowledge this is the largest cohort of HL patients from a single academic institution that serves primarily Hispanics. METHODS We located and retrospectively analyzed a total of 616 patients with diagnosis of Lymphoma (HL and NHL) by International Classification of Diseases (ICD) codes and identified 116 cases of HL; all the patients received care at UT Health San Antonio, between 2008-2018. Key variables for each patient included age, gender, race/ethnicity, comorbidities, insurance status, stage, BM and extranodal involvement, treatment received, outcome at 3 and 5 years and vitality status in 2018. Continuously distributed outcomes were summarized with the mean and standard deviation and categorical outcomes were summarized with frequencies and percentages. The significance of variation in the mean with disease category was assessed with one way ANOVA and the significance of associations between categorical outcomes was assessed with Pearson's Chi Square or Fisher's Exact test as appropriate. Multivariate logistic regression was used to model binary outcomes in terms of covariates and indicators of disease. All statistical testing was two-sided with a significance level of 5%. R1 was used throughout. The study was approved by the local Institutional Review Board. The findings will be available to patients, funders and medical community through traditional publishing and social media. RESULTS We identified 116 patients with HL, of which 73 were HI (63%), 43 NH (36%) and 1 not specified (1%). In regard to race, 92% identified as Caucasian, 4% as African American, 3% other and 1% Asian. The median age at diagnosis was 37.4, (SD 15.13). There were 49 females (42%) and 67 males (58%). The most common funding source was commercial insurance N=54 (47%), followed by a hospital payment plan N=30 (26%), Medicare N=16 (14%), unfunded N=13 (11%) and Medicaid N=3 (2%). Most prevalent co-morbidities were HTN N=28 (24%) and diabetes mellitus N= 23(20%); 50% of patients had no co-morbidities (N=63).At diagnosis ECOG of 0-1 was seen in 108 patients (93%); 8 were Stage I (7%), 39 stage II (33%), 32 stage III (28%), and 37 stage IV (32%). EBV was positive in 26 patients (22%). There were 15 patients that were HIV positive (13%), 54% with CD4 count <200, and 12 (75%) on antiretroviral therapy at diagnosis. Median PFS was 853.85 days (SD 912.92). We excluded patients who were lost to follow up or had not reached 3/5 years. At 3 year follow up there was: complete response in 37 HI (74%) vs 22 NH (92%); disease progression in 8 (16%) vs 0 (0%); death in 5 (10%) vs 2 (8%), respectively (p-value= 0.094). At 5 year follow up there was: complete response in 30 HI (77%) vs 17 NH (90%); progressive disease in 2 (5%) vs 0 (0); death 7 (18%) vs 2 (11%), respectively (p-value = 0.619). At the end of 2018, 41 HI (84%) were alive compared to 22 NH (88%) [p-value 0.74]. CONCLUSION Within the limitations of sample size, our study demonstrates that in the prevalently Hispanic population of our institution, HI patients with HL have no statistically significant difference in outcome when compared to NH patients. Disclosures No relevant conflicts of interest to declare.

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Hemophagocytic Lymphohistiocytosis: Update of Biology and Treatment Options

Blood ◽

10.1182/blood.v120.21.sci-9.sci-9 ◽

2012 ◽

Vol 120 (21) ◽

pp. SCI-9-SCI-9

Author(s):

Alexandra H. Filipovich

Keyword(s):

T Cells ◽

Hemophagocytic Lymphohistiocytosis ◽

Autosomal Recessive ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Treatment Options ◽

Clinical Signs ◽

The United States ◽

Activated T Cells ◽

High Incidence

Abstract Abstract SCI-9 Hemophagocytic lymphohistiocytosis (HLH) is a group of immunodeficiencies characterized by clinical signs and symptoms of extreme inflammation. HLH is now more widely recognized and no longer viewed as a disorder of young children only, as more adults are being diagnosed and treated. HLH is defined by a unique pattern of clinical findings. In addition to fevers, cytopenias, hepatitis, and splenomegaly, markedly increased levels of inflammatory markers in the blood (ferritin and sCD163 reflecting activation of antigen presenting cells; sIL2Ra and neopterin reflecting activation of T cells) constitute the collection of diagnostic criteria. Activation of inflammatory cells within the central nervous system (CNS) is found in approximately 50 percent of children at diagnosis and requires targeted therapy. In many cases immune defects affecting cytotoxicity of T cells and natural killer cells underlie the susceptibility to HLH. Autosomal recessive disorders include perforin deficiency (the major cytotoxin of the immune system), or defects in proteins involved in degranulation and exocytosis of perforin and granzyme B (MUNC 13–4, MUNC18-2, STX11, Rab27a). The latter proteins are involved in degranulation generally within the hematopoietic system, thus impacting the function of neutrophils and platelets as well. A rare defect of granulogenesis, Chediak Higashi syndrome, is also associated with a high incidence of HLH. Two forms of X-linked lymphoproliferative syndrome (XLP1 – SAP deficiency, and XLP2 – XIAP deficiency), as well as the rare autosomal recessive disorder ITK (IL-2 inducible T cell kinase) deficiency, are characterized by a high incidence of Epstein-Barr virus-driven HLH and lymphoproliferation. A common pathogenic mechanism underlying these consequences has not yet been elucidated. Effective initial treatment for HLH consists of cytotoxic and anti-inflammatory agents. The most widely used over the past 20 years has been a combination of CNS-penetrating steroid (Decadron) and etoposide. Another approach has been to use anti-thymocyte globulin (ATG) as induction therapy. Both treatments have resulted in approximately 60 percent responses during the first month of therapy. Supportive care with broad-spectrum antimicrobials is a critical adjunct. More recently, a new induction protocol—hybrid immunotherapy for HLH, combining the features of early ATG followed by etoposide, with steroids—has been opened in the United States (http://clinicaltrials.gov/ct2/show/NCT01104025) and Europe. However, HLH persists or reactivates in nearly half of patients as immune suppression is reduced. While a common approach to reactivation is to reintensify previous therapy, no clear guidelines have been developed for this complication. The use of Campath, a humanized monoclonal anti-CD52 antibody, as salvage therapy prior to hematopoietic cell transplantation (HCT) is being tested, as both activated T cells and activated monocyte/macrophages (histiocytes) are targeted through CD52. Historically, the three-year survival after HCT in patients treated with HLH-94 was 60 percent. More recently, use of Campath-based reduced intensity conditioning protocols have led to improved results after HCT. Campath has the advantage of reducing graft-versus-host disease if properly timed prior to HCT. In a recent contemporaneous series of HCT from unrelated adult donors, three-year posttransplant survival improved from 43 percent to 92 percent with no early transplant-related mortality. Disclosures: No relevant conflicts of interest to declare.

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Carfilzomib and Bortezomib Containing Regimens Yield High Rates Of MRD Negative Autologous Hematopoietic Progenitor Cell (HPC) Grafts In Multiple Myeloma (MM) and High Risk Smoldering Myeloma (SMM)

Blood ◽

10.1182/blood.v122.21.2030.2030 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2030-2030

Author(s):

Nishant Tageja ◽

Neha Korde ◽

Constance Yuan ◽

Kristen Cole ◽

Jennifer Hsu ◽

...

Keyword(s):

Flow Cytometry ◽

Stem Cell ◽

High Risk ◽

Tumor Cell ◽

Peripheral Blood ◽

Conflicts Of Interest ◽

Hematopoietic Progenitor Cell ◽

Myeloma Cells ◽

Cd34 Cells ◽

The Mean

Abstract Background Regimens incorporating modern anti-myeloma drugs, such as carfilzomib (CFZ) and bortezomib (BOR), produce rapid, deep and durable responses in newly diagnosed myeloma patients but their effect on collection of autologous HPC is not well known, including minimal residual disease (MRD) testing of stem cell grafts. Employing older induction regimens (such as VAD), less sensitive flow cytometry techniques detected circulating myeloma cells in 38-46% of autologous HPC grafts (Stewart, et al. JCO. 2001 and Bourhis, et al. Haematologica. 2007). We hypothesized that the use of modern CRd combination therapy including Carfilzomib (CFZ)-Lenalidomide (LEN)-Dexamethasone (DEX) would significantly lower the rates of HPC product contamination. Methods Thirty-six patients, including 29 with MM and 7 with high-risk SMM, underwent HPC mobilization and collection following induction with CRd (n=30), LEN-BOR-DEX (RVd, n=4), Cyclophosphamide-BOR-DEX (CyBorD, n=1) and Cyclophosphamide-BOR-Prednisone (CyBorP, n=1). For HPC mobilization, all patients received 5 days of filgrastim at 10-16 mcg/kg/dose. A combination of the patient’s weight and a peripheral blood CD34 count after 4 doses was used to determine the likelihood of collecting > 4 x106 CD34+ cells/ kg in a single apheresis procedure after a fifth filgrastim dose, according to a previously published algorithm from our institution. Only subjects predicted to require > 1 apheresis by the algorithm received Plerixafor (PLX) at 240 mcg/kg/dose on the fifth day along with the fifth filgrastim dose. HPC collection occurred on day 6, 8 hours after the last mobilizing agent(s) administration. Product contamination with myeloma cells (i.e. MRD status) was evaluated using multi-parameter flow cytometry with a minimum of 3 x 106 events obtained (sensitivity detection rate 1 x 10-5) to examine expression of 9 antigens by the plasma cells. Results The median age at mobilization was 56.2 years (range 40-73) and 19 (53%) were male. At the time of HPC collection, 20 (55%) patients were in sCR/CR/nCR, 11 (30%) had VGPR with 4 PR (11%) and 1 SD (3%). The mean CD34+ cells in the peripheral blood were 33/uL on day 5 and 55/uL on day 6 for the whole cohort. Thirteen (36%) patients did not need PLX. Interestingly, the mean CD34+ count dropped by a mean of 2% from D5 to D6 in patients not receiving PLX while, as expected, it increased by 304% in those who did. The median number of CD34+ cells collected was 6.86 million/kg (range 2.6-12.5) for the whole cohort, (6.6 million/kg without PLX and 7.52 million with PLX p=0.46). Thirty-three of 36 patients (92%) achieved a collection of > 4 million cells /kg in a single apheresis procedure. The 30 patients treated with CRd had a median of 5 (range = 3-7) prior cycles containing LEN with a median of 12 days (range 1-34) between mobilization and last LEN dose. Only 2 of 36 (5%) products were found to have evidence of tumor cell contamination (i.e. MRD positive) using sensitive multiparameter flow cytometry, one patient in PR after 6 cycles of CRd and a second patient in CR after 5 cycles of RVd. Conclusions Modern anti-myeloma therapies, such as CRd and RVd, allow adequate HPC collection in a single apheresis procedure in most cases and improve the quality of the HPC product with greatly reduced tumor cell contamination compared to historical controls. Indeed, 34/36 (94%) patients treated with modern anti-myeloma therapy collected an MRD negative HPC product. Future prospective studies are needed to assess whether autologous stem cell transplants (ASCT) using tumor-free HPC products collected in the era of modern induction therapies have better outcomes. Disclosures: No relevant conflicts of interest to declare.

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Baseline Symptoms, Female Sex, and Younger Age Are Correlated with Higher Levels of Peri-Collection Pain, Symptoms, and Persistent Discomfort One Year after Related Donor BM and PBSC Donation: An Analysis of the Related Donor Safety Study (RDSafe)

Blood ◽

10.1182/blood.v124.21.3847.3847 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3847-3847

Author(s):

Michael A. Pulsipher ◽

Brent R. Logan ◽

Deidre M. Kiefer ◽

Pintip Chitphakdithai ◽

Galen E. Switzer ◽

...

Keyword(s):

Conflicts Of Interest ◽

The United States ◽

P Value ◽

Unrelated Donor ◽

Moderate Pain ◽

Safety Study ◽

Peripheral Blood Stem Cells ◽

Donor Safety ◽

Related Donor ◽

Pain Symptoms

Abstract Prospective data regarding donation related toxicities and time to recovery in related donors (RDs) of bone marrow (BM) and peripheral blood stem cells (PBSC) are limited, in contrast to significant data available regarding unrelated donor experiences. To address this lack of data in RDs, the NHLBI-funded Related Donor Safety Study (RDSafe; NCT00948636) prospectively enrolled RDs of all ages between 2010 and 2013 at 54 transplant centers in the United States. RDs were assessed for pre-donation comorbidities and health status, and then followed for 1 year after donation, collecting detailed information on adverse events, pain levels and 10 collection-related NCI-CTC symptoms. This report describes baseline, peri-donation, and through 1 year post pain/symptoms for RDs aged 18-60: 124 BM (38 centers, med age 33, 48% female) and 919 PBSC (42 centers, med age 49, 44% female). Results: About 20% of RDs reported pain and NCI-CTC symptoms at baseline, mostly grade 1, with females reporting pain/symptoms more often than males (see figures). Pain occurred in approximately 80% of donors surrounding collection with other symptoms occurring in 50-70% of donors. Pain and symptoms persisted in 10-20% of RDs at 1, 6, and 12 months; pain/symptoms returned to baseline in only a few categories assessed, but mostly remained elevated from baseline at 1 year. In addition, for both males and females, at 1 year grade 2-4 pain or symptoms were 2-3 times baseline rates. Multivariate analysis was performed on PBSC donors, where numbers were sufficient to look at key risk factors (see table). Females had more grade 3-4 pain at collection, and grade 2-4 pain and symptoms at 1 year. Age differences were noted, with RDs age 30-39 experiencing the highest amount of pain and symptoms and RDs age 50-60 experiencing less pain compared to donors aged 18-29. Pain or symptoms at baseline were important predictors of higher levels of reported pain/symptoms, respectively, during the collection and also higher risk of grade 2-4 pain at 1 year. Conclusions: One in 5 RDs have mild/moderate pain and/or symptoms at baseline, and the presence of pain/symptoms at baseline increases risk for experiencing higher levels of pain/symptoms during collection. Although the majority of RDs return to baseline status within a month of donation, >10-20% of RDs have lingering pain/symptoms 6-12 months after donation, and rates of grades 2-4 pain and symptoms at 1 year are more than double baseline. Females have higher grades of pain with collection and more grade 2-4 pain and symptoms at 1 year compared to males. RDs should be informed of the risk of mild/moderate pain/symptoms lingering through the first year after donation. Ongoing efforts to correlate baseline comorbidities of RDs with outcomes should allow RDs to be better informed of risk and potentially identify clinical risk profiles where RDs should be deferred. *Pain = max grade 2-4 or 3-4 2 days post-donation of BM or day+5 of PBSC collection (collection day 1). **Symptoms = fever, fatigue, rash, local site reactions, nausea, vomiting, anorexia, insomnia, dizziness, and syncope Table 1. MV Analysis of PBSC RDs for pain and donation-related symptoms: Odds Ratio (p-value). Pain* Symptoms** day+5 Grd 2-4 day+5 Grd 3-4 1yr Grd 2-4 day+5 Grd 2-4 1yr Grd 2-4 Female 1.667 (0.010) 1.667 (0.016) 1.887 (0.041) Age (0.001) (0.008) (<0.001) Age 18-29 1.0 1.0 1.0 Age 30-39 0.76 (0.306) 2.2 (0.036) 2.48 (0.008) Age 40-49 0.68 (0.115) 1.46 (0.283) 1.49 (0.216) Age 50-60 0.45 (<0.001) 0.93 (0.836) 0.93 (0.830) Baseline pain overall (0.001) (0.004) (<0.001) Baseline pain Grd 0 1.0 1.0 1.0 Baseline pain Grd 1 2.2 (<0.001) 2.6 (0.06) 2.95 (<0.001) Baseline pain Grd 2-4 4.73 (<0.001) 4.4 (0.002) 3.95 (<0.001) Baseline sx overall (<0.001) Baseline sx Grd 0 1.0 Baseline sx Grd 1-4 2.16 (<0.001) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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A Comparative Study of Active Management of the Third Stage of Labor IV Methergine and IM Oxytocin

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i45a32743 ◽

2021 ◽

pp. 267-272

Author(s):

K. Sharmila

Keyword(s):

Blood Loss ◽

The United States ◽

Active Management ◽

P Value ◽

Negative Effects ◽

The Third ◽

Third Stage Of Labor ◽

Group I ◽

Third Stage ◽

The Mean

Postpartum haemorrhage (PPH) has been more common over the last three decades, accounting for 11% of all pregnancy-related deaths in the United States. In the third stage of labour, risk classification and active management are crucial preventative techniques. To avoid negative effects, a multidisciplinary approach to PPH patient care is required. To treat uterine atony, uterotonic medicines like oxytocin are used in combination with manipulative procedures like uterine massage and balloon tamponade. The amount of blood loss, duration of the third stage, need for MRP, incidence of PPH, need for repeated oxytocics, and its side effects were measured in Group I 100 women who were administered injection oxytocin 10 IU injection methergin 0.2 mg IV within one minute of the baby's delivery. The mean blood loss at vaginal delivery in Group I was 100-150 ml and in group I P value 0.027, which was statistically significant .In Group II was 160-200 ml with P value 0.036, which was statistically significant. The mean duration of third stag labour in Group 1 was 124.6 min and Group 2 was 144.8 min intravenous methergin is a better uterotonic when compared to intramuscular oxytocin to reduce the amount of blood loss at delivery and prevent complications like atonic PPH.

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Association of University Reopening Policies with New Confirmed COVID-19 Cases in the United States

10.1101/2020.12.11.20247353 ◽

2020 ◽

Author(s):

Yang Li ◽

Cheng Ma ◽

Weijing Tang ◽

Xuefei Zhang ◽

Ji Zhu ◽

...

Keyword(s):

Multivariate Regression ◽

Regression Models ◽

Positive Association ◽

The United States ◽

P Value ◽

County Level ◽

Hybrid Mode ◽

County Population ◽

Public Health Officials ◽

The Mean

AbstractReopening of universities in the U.S. has been controversial in the setting of the coronavirus disease 2019 (COVID-19) pandemic. We leveraged several publicly available data sources to study the association of county-level new confirmed COVID-19 case rates since September 1st and the number of students returning to campus across 2,893 U.S. counties with and without universities. In 1,069 U.S. counties with universities, we also studied the association of different reopening policies (online, in-person, hybrid) on new confirmed COVID-19 cases. Multivariate regression models estimated both effects of university reopening and different reopening policies. Mean number of daily confirmed cases per 10,000 county population was 1.51 from August 1st to August 31st, and 1.98 from September 1st to October 22nd. Mean number of students returning to universities was 2.1% (95% CI, 1.8% to 2.3%) of the county population and the number of students returning to campus had a positive association (β = 2.006, p-value < 0.001) with new confirmed COVID-19 cases within the local county region where the institution resided. For U.S. counties with universities, the mean proportion of online enrollment within each county was 40.1% (95% CI, 37.4% to 42.8%), with most students enrolling in-person or hybrid mode. In comparison to holding class in-person, reopening universities online (β = -0.329, p-value < 0.001) or in a hybrid mode (β = -0.272, p-value = 0.012) was negatively associated with new confirmed COVID-19 cases. These findings could help public health officials consider policies to mitigate additional waves of infection during the upcoming winter.Significance StatementOur study finds that higher numbers of students returning to campus was associated with an increase in new confirmed COVID-19 cases; reopening online or partially online was associated with slower spread of the virus, in comparison to in-person reopening. These findings could provide guidance for policymakers on universities’ reopening in upcoming semesters.

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Over Expression of MN1 Accelerates Leukemia Onset and Confers Resistance to Chemotherapy by Suppression of p53 and Bim

Blood ◽

10.1182/blood.v118.21.2501.2501 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2501-2501

Author(s):

Timothy Pardee

Keyword(s):

Bone Marrow ◽

Conflicts Of Interest ◽

The United States ◽

Retroviral Vectors ◽

Genetic Alterations ◽

P Value ◽

Over Expression ◽

Resistance To Chemotherapy ◽

Worse Prognosis

Abstract Abstract 2501 Acute myeloid leukemia (AML) is an aggressive malignancy of immature myeloid precursors that leads to progressive marrow failure and death. This disease will affect approximately 12,950 people this year in the United States, causing 9,050 deaths. The most common treatment is combination chemotherapy containing cytarabine (Ara-C) and an anthracycline. Resistance to these therapies is a major problem and most patients diagnosed with AML will ultimately die from resistant disease. AML is a genetically diverse malignancy and karyotype can be used to delineate prognosis. There is a clear link between chromosomal abnormalities and resistance to chemotherapy as complete remission rates are significantly different between groups. Additionally, there are now multiple submicroscopic genetic alterations that have been found to effect prognosis. These alterations can be mutations, over or under expression of a particular gene. MN1 is a transcription co-factor and several studies have demonstrated its over-expression confers a worse prognosis. High MN1 expressers were less likely to achieve a remission and had lower 3 year survival rates. Additionally, over expression of MN1 in murine bone marrow leads to AML in transplanted recipients and predicts for resistance to ATRA in elderly AML patients. The effect of MN1 on response to standard chemotherapy is currently unknown. To determine the effect of MN1 expression on therapy response we infected murine MLL-ENL driven AML cells with retroviral vectors that expressed MN1. When partially infected populations were exposed to a titration of either Ara-C or doxorubicin MN1 expressing cells were significantly enriched compared to untreated controls. When cells were exposed to a titration of Ara-C the MN1 expressing cells were enriched up to1.69 fold and when exposed to doxorubicin were enriched up to 3.80 fold. Both results were highly statistically significant with p values of 0.004 and < 0.0001. Consistent results were obtained with repeated infections and with separately derived MLL-ENL lines. Additionally, MN1 was able to confer therapy resistance to anthracycline resistant Flt3-ITD expressing cells suggesting non-overlapping mechanisms. Purified populations of cells expressing MN1 were resistant to Ara-C when compared to the parental leukemia (IC50 175.6nM vs 67.28nM) and highly resistant to doxorubicin. Consistent with these results human OCI-AML3 cells expressing MN1were enriched by 1.6 fold when exposed to doxorubicin, a highly significant result with a p value of 0.0002. In contrast a control vector without MN1 was not significantly enriched. In vivo when mixed leukemia cells were injected into syngeniec recipients MN1 expressers were significantly enriched in the femoral bone marrow of treated animals compared to controls. Treated animals had 90.58% (+/−0.66) MN1 expressing blasts compared to 55.38% (+/−5.25) in controls. This result was highly statistically significant with a p value of < 0.0001. This observation was reproducible in a separately derived MLL-ENL driven cell line. Additionally, the engraftment of MLL-ENL and Flt3-ITD expressing cells was significantly increased by MN1 expression leading to shorter survival in recipient animals despite the already highly aggressive nature of the parental leukemia. When MN1 expressing cells were exposed to doxorubicin or Ara-C they displayed significantly lower Annexin V positivity consistent with an attenuated apoptotic response (3.65 vs 34.79, p=<0.0001). When we examined BH3 only family member induction following exposure to Ara-C and doxorubicin we found significantly decreased levels of Bim induction by QPCR in cells expressing MN1. Similarly, stabilization of p53 following treatment was blunted in MN1 expressers as was induction of its downstream targets p21 and MDM2. Importantly the amount of DNA damage induced by doxorubicin as assessed by γH2AX foci was not different between MN1 expressing cells and the parental leukemia. These data suggest that over expression of MN1 confers resistance to both Ara-C and doxorubicin in vitro and in vivo by suppression of Bim induction and p53 response. These observations suggest a biological explanation for the clinical observation that it confers a worse prognosis. Disclosures: No relevant conflicts of interest to declare.

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Pre-Transplant Ferritin, Albumin and Platelet Count Add Prognostic Information to Comorbidities for Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes: A Multi-Center Discovery-Validation Study

Blood ◽

10.1182/blood.v124.21.421.421 ◽

2014 ◽

Vol 124 (21) ◽

pp. 421-421

Author(s):

Jennifer E. Vaughn ◽

Barry E. Storer ◽

Philippe Armand ◽

Roberto Raimondi ◽

Christopher J Gibson ◽

...

Keyword(s):

Cell Transplantation ◽

Validation Study ◽

Hematopoietic Cell Transplantation ◽

Disease Risk ◽

Conflicts Of Interest ◽

Karnofsky Performance Status ◽

Statistical Significance ◽

Prognostic Information ◽

Allogeneic Hct ◽

C Statistic

Abstract Albumin, ferritin, and peripheral blood counts broadly capture health status in patients undergoing allogeneic stem cell transplantation (HCT). Whether they add any prognostic information to the HCT-Comorbidity Index (HCT-CI) is unknown. We analyzed the independent prognostic role of a group of 5 biomarkers (ferritin, albumin, absolute neutrophil count (ANC), hemoglobin (Hgb), and platelet (Plt) count) in pts given allogeneic HCT for hematologic malignancies. This was a multi-center, retrospective discovery-validation study comprising data from 3917 recipients of allogeneic HCT at the Fred Hutchinson Cancer Research Institute (FHCRC) (n=1789) and Dana Farber Cancer Institute (DF) (n=716) in the US and the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) (n=1412) in Italy (Table 1). Proportional hazard models were used to estimate the hazards of non-relapse mortality (NRM) and survival after adjustment for the HCT-CI, donor type, CMV serostatus, regimen intensity, age, disease risk and Karnofsky Performance Status (KPS). These were stratified by institution. Model performances were tested by c-statistic estimates. In an initial analysis within the FHCRC population, ANC of <500 and Hgb of < 9 were not associated with outcomes in the models. Alternatively, ferritin >1000 (HR 1.98; p=0.0003) and >2500 (HR 1.97; p=0.0005); albumin <3.5 (HR 1.63; p<0.00001) and <3.0 (HR 1.73 p<0.0001); and Plt <100k (HR 1.65; p<0.0001), <50k (HR 1.52; p<0.0001) , and <20K (HR 1.54; p<0.008) were all statistically significantly associated with NRM. Results were validated in a larger population from DF and GITMO. In multivariate models, adjusted for previously mentioned variables, ferritin >2500 and incremental decreases in albumin and Plt counts had statistically significant associations with both NRM and survival (Table 2). Of note, HCT-CI scores (2, 3 and >4) also retained significant associations with NRM and survival in the presence of the three biomarker values and in both cohorts. Subsequent multivariate analyses stratified the whole cohort (n=3917) into a training (n=2352) and a validation (n=1407) set. In both sets, albumin <3.5, plts <100K, and ferritin >2500 had statistical significance associations with NRM and survival. Each of the three biomarker values were subsequently assigned a weight of 1 following the same equation used to develop the HCT-CI. The augmented HCT-CI/biomarker index had higher c-statistic estimate (0.61) for prediction of NRM compared to the HCT-CI alone (0.58) in the validation set. Ferritin, albumin, and Plt counts are simple and valid prognostic biomarkers for transplant outcomes and should be considered in combination with the HCT-CI in risk assessment prior to allogeneic HCT. The physiology behind these associations warrants further investigation to identify areas of intervention that may improve outcomes. Table 1: Pt characteristics FHCRC(N=1789) DF/GITMO(N=2128) N (%) N (%) Donor Related 900 (50) 1062 (50) Unrelated 889 (50) 1053 (50) Disease risk Low 740 (41) 866 (43) High 1049 (59) 1157 (57) Age < 50 1025 (57) 1120 (53) ≥ 50 764 (43) 1008 (47) Conditioning MA 983 (55) 1100 (52) RIC/NMA 806 (45) 1004 (48) Pt CMV - 773 (43) 505 (24) + 1016 (57) 1581 (76) KPS ≤ 90 691 (39) 644 (33) 90-100 1098 (61) 1304 (67) Table 2: Multivariate analysis showing the associations between biomarkers and NRM and survival. NRM Survival Marker HR1 P1 HR1 P1 FHCRC Albumin ≥3.5 1.0 1.0 <3.5 - 3.0 1.44 0.002 1.45 <0.0001 <3.0 1.77 <0.0001 1.77 <0.0001 Unk 1.15 0.38 1.19 0.11 Plts ≥100K 1.0 1.0 <100K – 50K 1.48 0.0007 1.28 0.003 <50K – 20K 1.49 0.003 1.37 0.001 <20K 1.64 0.005 1.58 0.0004 Unk 0.66 0.47 0.48 0.14 Ferritin ≤1000 1.0 1.0 >1000 - 2500 1.60 0.03 1.70 0.0006 >2500 2.08 0.001 1.63 0.007 Unk 1.42 0.03 1.44 0.002 HCT-CI 0 1.0 1.0 1 1.29 0.12 1.31 0.02 2 1.50 0.01 1.42 0.001 3 2.29 <0.0001 2.04 <0.0001 ≥ 4 2.94 <0.0001 2.42 <0.0001 DF/GITMO Albumin ≥3.5 1.0 1.0 <3.5 - 3.0 1.60 0.0001 1.36 0.0005 <3.0 2.77 <0.0001 2.18 <0.0001 Unk 1.61 0.01 1.11 0.49 Plts ≥100K 1.0 1.0 <100K – 50K 1.08 0.56 1.02 0.85 <50K – 20K 1.17 0.28 1.21 0.06 <20K 1.38 0.04 1.35 0.009 Unk 0.64 0.10 0.82 0.28 Ferritin ≤1000 1.0 1.0 >1000 - 2500 1.11 0.43 1.23 0.02 >2500 1.60 0.002 1.69 <0.0001 Unk 1.13 0.33 1.12 0.19 HCT-CI 0 1.0 1.0 1 1.31 0.05 1.14 0.19 2 1.29 0.10 1.25 0.04 3 1.48 0.006 1.46 0.0001 ≥ 4 1.74 <0.0001 1.66 <0.0001 1 Adjusted for donor , CMV serostatus , regimen intensity , age , disease risk , KPS ; stratified on institution. Unk=Unknown Disclosures No relevant conflicts of interest to declare.

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Incidence and Outcomes of Acute Transfusion Reactions in Hospitalized Patients in the United States

Blood ◽

10.1182/blood-2020-138982 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Rohit Kumar ◽

Sindhu Malapati ◽

Sunny R K Singh ◽

Bokhodir Mamedov ◽

Myra R Shah ◽

...

Keyword(s):

Risk Factors ◽

Conflicts Of Interest ◽

Multivariate Logistic Regression Analysis ◽

The United States ◽

Hospitalized Patients ◽

P Value ◽

Continuous Variables ◽

Blood Products ◽

Increased Risk ◽

Transfusion Reactions

Introduction Acute transfusion reactions (ATRs) have a broad spectrum of presentations ranging from benign to life-threatening. Due to the rarity of these reactions, there is a paucity of data regarding their incidence and clinical outcomes. The objectives of this study were to determine the incidence of ATRs, its risk factors, and associated mortality. Methods: We reviewed the National Inpatient Sample (NIS) database 2014 for admissions where the patient (>=18 years old) was transfused blood products. The NIS is a large publicly available all-payer inpatient healthcare database designed to produce U.S. regional and national estimates of inpatient utilization, access, charges, quality, and outcomes. ATRs were identified using ICD-9 CM codes for transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), febrile non-hemolytic transfusion reactions (FNHTR), acute infections, anaphylaxis, and acute hemolytic reaction. Pearson's chi-square and student's t-test were used to compare categorical and continuous variables between hospitalizations with versus without ATRs, respectively. Multivariate logistic regression analysis was done to determine the risk factors for common ATRs (TACO, TRALI, and FNHTR). A multivariate cox proportional model was built to compare the mortality of two study groups. A 2-sided p-value ≤ 0.05 was considered significant. Results: A total of 2,134,691 hospitalizations were associated with the transfusion of blood products. ATRs were documented in 0.2% of the hospitalizations (TACO 0.08%, TRALI 0.06%, FNHTR 0.09%, others 0.003%). The group that had ATRs was slightly younger (median age 67 vs 68 years, p=0.002), had the same proportion of females (58.3% vs 55.3%, p=0.055), less comorbidity score (28.7% vs 31.7% had Charlson Comorbidity Index >3, p=0.042) and more critically ill (17.8% vs 10.5% on mechanical ventilation, p<0.001) compared to group without ATRs. Hospitalizations with ATRs had longer median length of stay (7 vs 6 days, p<0.001) and higher median hospital cost ($64,399 vs $53,912, p<0.001) compared to without ATRs. The risk factors for common ATRs (odds ratio, OR) are mentioned in the table. ATRs were not associated with increased risk of mortality (combined HR 0.89 95%CI 0.71-1.12, p=0.321). Conclusions: Nationally, the incidence of ATRs is low in hospitalized patients and it is not associated with increased mortality. This large database analysis gives insight into the risk factors associated with different ATRs. Disclosures No relevant conflicts of interest to declare.

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