Sarode, Ravi

Abstract Background Red blood cell (RBC) transfusion may be lifesaving, however transfusion-transmitted infections (TTI) and transfusion-associated graft-versus-host disease (TA-GVHD) still pose a threat despite current donor selection and testing requirements. Amustaline (S-303)/glutathione (GSH) pathogen reduction (PR) is designed to inactivate infectious microbes and leukocytes in RBCs. The RedeS study evaluates the safety and efficacy of amustaline/GSH PR-RBCs compared to conventional RBCs in a broad spectrum of patients requiring acute and/or repeated RBC transfusion support. Methods RedeS is a Phase 3, prospective, multi-center, randomized, double-blind, active-controlled, parallel-design study, with a 6-month extension option to evaluate patients requiring repeated transfusions including red cell exchange (RCE).Eligible subjects will be stratified according to site, baseline bleeding status and participation in the extension period. The study arms include a transfusion period of 28-days for anemia with any bleeding or non-bleeding patients or a 28-day+6-month extension for non-bleeding patients with chronic anemia requiring repeated simple transfusions, or for patients with sickle cell disease (SCD) expected to receive three RCE procedures. The study will seek to enroll 600-800 subjects in the overall safety analysis, including ~140 repeatedly-transfused subjects in the 6-month extension including up to 30 subjects receiving three RCE procedures. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days after the last study transfusion, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to PR-RBCs. The primary efficacy endpoint is the hemoglobin (Hb) increment in subjects who are non-bleeding at baseline, adjusted for the grams of Hb transfused and averaged over multiple transfusions. With 352 evaluable transfused non-bleeding subjects (176 per treatment group) from either arm, the study will have 80% power to demonstrate non-inferiority, defined as a Hb increment treatment difference of no more than 15% of the Control group mean, assuming a Control arm coefficient of variation of 50%. Discussion RedeS will characterize the safety of amustaline/GSH PR-RBCs and is designed to demonstrate the non-inferiority of PR-RBCs to conventional RBCs with respect to Hb increment, a common pragmatic clinical assessment of RBC transfusion effectiveness.

Background: Transfusion has a persistent low risk of transfusion-transmitted infection and transfusion-associated graft- versus -host disease that may be addressed using pathogen reduction. The Red Cell Pathogen Inactivation (ReCePI) trial tested whether amustaline/glutathione pathogen-reduced red cells are noninferior to conventional transfusions for support of acute surgical blood loss. Methods: A phase 3, double-blinded, noninferiority trial randomized cardiac or thoracic–aorta surgery patients with increased risk of red cell transfusion to receive pathogen-reduced or conventional red cells during and for 7 days postsurgery. The primary endpoint was the proportion of patients with acute kidney injury (AKI), which is defined as an increase from baseline of greater than or equal to 0.3 mg/dl serum creatinine within 48 h of surgery. Noninferiority was claimed if the upper bound 95% CI of the treatment difference was less than half (50%) of the observed conventional arm incidence. Adverse events and treatment-emergent red cell antibodies were assessed for 28 and 75 days, respectively. Results: A total of 581 subjects were randomized, and 321 (55%) were transfused with study red cells. Transfused subjects in both arms had similar baseline demographics, medical histories, hemoglobin levels, and surgical procedures. Hemoglobin day 3 nadir levels (8.6 g/dl [7.8 to 9.2] in the pathogen-reduced arm; 8.4 g/dl [7.8 to 9.3] in the conventional arm; P = 0.52) were comparable. Incidence of AKI by 48 h was 46 of 157 (29.3%) in the pathogen-reduced arm and 45 of 161 (28.0%) in the conventional arm (treatment difference, 0.7%; 95% CI, −8.9 to 10.4%; noninferiority margin, 14.0%; P = 0.001 for noninferiority). AKI within 7 days by Kidney Disease Improving Global Outcomes staging criteria was not different (59 of 159 [37.1%] in the pathogen-reduced arm; 55 of 162 [34.0%] in the conventional arm; P = 0.53), but stage III was more common in the pathogen-reduced arm (pathogen-reduced arm, 15 of 159 [9.4%]; conventional arm, 7 of 162 [4.3%]; P = 0.075). Of 159 pathogen-reduced red cell recipients, 5 (3.1%) developed specific, low-titer antibodies without evidence of hemolysis. Conclusions: The incidence of AKI in recipients of pathogen-reduced red cells was noninferior to conventional red cell transfusion. Treatment-emergent antibodies were uncommon and not clinically significant.

Introduction: Red blood cell (RBC) transfusion is a lifesaving intervention with a low but persistent risk of transfusion-transmitted infection. Amustaline/glutathione RBC pathogen-reduction (PR) technology is designed to proactively inactivate a broad spectrum of viruses, bacteria, protozoa and leukocytes by chemically crosslinking nucleic acids and preventing replication and transcription. The Red Cell Pathogen Inactivation (ReCePI) trial was a Phase III, double-blinded, randomized non-inferiority study comparing PR and conventional RBCs for the support of acute anemia. Methods/Study Design: Complex cardiac or thoracic-aorta surgery patients received conventional (Control) or PR RBCs (Test) during and for 7 days after surgery. The protocol was conducted with ethics committee approval at all participating centers and written informed consent from all participants. Hemoglobin levels, blood utilization and serum creatinine were assessed as indicators of efficacy and oxygenation of tissues (Karkouti et al. Br J Anaesth. 2012; 109 Suppl 1: i29-i38). The primary endpoint was the incidence of acute kidney injury (AKI) measured as change in serum creatinine from baseline within 48 hours of surgery, a predictor of adverse postoperative outcomes including mortality by Day 30 post-surgery (Lassnig et al. Am Soc Nephrol 2004; 1597-1605). Secondary endpoints included AKI occurring up to 7 days post-surgery (KDIGO Clinical Practice Guideline for AKI, Kidney Inter, Suppl. 2012;2:1-138); death or the need for renal replacement therapy by 30 days post-surgery; PR RBC-specific antibodies; and death by day 75 post-surgery. With >292 subjects enrolled, the study had 80% power to demonstrate non-inferiority, assuming an AKI incidence of 30% with conventional RBCs and a non-inferiority margin of half the conventional RBC rate. Under these circumstances, an absolute treatment increase of 5% in the AKI rate in the PR RBC arm would fail the non-inferiority test. This work was supported by a contract with the US Biomedical Advanced Research and Development Authority (HHS010020160009c) with Cerus Corporation. Results: Five-hundred and eighty-one subjects were randomized and 321 (55%) transfused in 18 US hospitals. In the modified intent-to-treat analysis subjects receiving Test and Control RBCs had similar median [IQR] total blood loss (1500 [940-2475] mL Test, 1733 [1060-2880] mL Control, p=0.310) and comparable median hemoglobin levels at baseline and immediately post-surgery (9.8 [8.9-10.9] g/dL Test, 9.6 [8.6-10.6] g/dL Control, p=0.157) and for 7 days after surgery, The PR RBC arm was transfused with fewer RBCs, measured as total RBC Hb transfused over 7-days (169.0 [102.0-240.0] g Hb PR arm, 188.0 [126.0-295.0] g Hb, conventional RBC arm, p=0.008). The incidence of AKI was 29.3% (46/157) for Test and 28.0% (45/161) for Control. The treatment difference was 0.74% (95% CI -8.9, 10.4%, non-inferiority margin 14.0%, p=0.001 for non-inferiority). Non-inferiority was also achieved by the per protocol analysis. Average mean change in serum creatinine within 48 hours of surgery was comparable (Test 0.020, Control 0.23 mg/dL, P=0.515). Adverse events, serious adverse events and deaths on study were not different. Five of 159 (3.1%) PR RBC recipients developed low titer PR RBC-specific antibodies without clinical signs of hemolysis. Flow cytometry analysis revealed persistent circulating PR RBCs with uniform antigen loss (modulation). Low level human IgG antibody binding was demonstrated in 3 of 5 subjects. Conclusions: PR RBCs showed equivalent hemoglobin support for acute bleeding patients undergoing cardiac or thoracic-aorta surgery while using less transfused total RBC Hb over 7 days. The incidence of AKI in patients transfused with PR RBCs was non-inferior to that observed with conventional RBCs, indicative of effective tissue oxygenation. Treatment-related antibodies to PR-RBC were observed only in Test subjects, the antibodies were low titer, transient, without clinical hemolysis, and persistent circulating PR RBCs were detected with modulated low level acridine antigen expression (www.clinicaltrials.gov #NCT03459287).

Abstract Background Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leucocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. Methods ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, paralleldesign, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to Day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥0.3 mg/dL (or 26.5 µmol/L) from presurgery baseline within 48±4 hours of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen reduced RBCs through 75 days after the last study transfusion. With ≥292 evaluable, transfused patients (>146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. Discussion RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBC.

Abstract SERF-TTP is the first prospective case-control study to investigate epidemiology, risk factors & outcomes in patients with first episode of idiopathic TTP. METHODS: Each case of TTP is identified upon referral for therapeutic plasma exchange (TPE). Exclusion criteria include organ or allogeneic stem cell transplant, anti-neoplastic therapy or malignancy. 2 age & gender-matched controls are identified for each case. Epidemiologic information, lab data & plasma samples are collected from each case. Case & control data are collected by standardized interview. Relative risk & 95% CI computed by chi-squared tests. ADAMTS13 activity & inhibitor are centrally measured on pre-TPE samples. ADAMTS13 activity is measured by FRETS-vWF73 assay (Peptides Int.). ADAMTS13 inhibitor is assessed by Technozym ADAMTS13 INH ELISA (Technoclone). RESULTS: Data is available for 67 cases & 138 controls. The median age of cases is 40, & 82% are female. Medical history & exposures are shown in Table 1. Clinical & lab characteristics vary by ADAMTS13 activity (Table 2). Low titer ADAMTS13 inhibitors are detectable in some patients with normal ADAMTS13 activity. 30 day survival of cases is 95.7%. Adverse reactions to TPE occur in 59% of patients, most commonly allergic(85%) or citrate-related reactions(65%). 14.7% had a venous access complication, 50% were catheter-related thromboses. 10% of all adverse events required an ICU admission. CONCLUSIONS: Preliminary results from the case-control study suggest that predisposing factors for the development of TTP include recent infection or connective tissue disorder. Cardiovascular disease, prior history of venous thrombosis, clopidogrel use and lower income are more common in TTP cases than controls. Patients with normal ADAMTS13 activity are more likely to present with higher platelet count, abnormal renal function and neurologic symptoms. Case & Control Characteristics Cases (n=67) Controls (n=138) Relative Risk (95% CI) Medical History Connective Tissue Disease 11.9% 2.2% 5.4 (1.5–20.0) Cardiovascular Disease 13.4% 3.6% 3.7 (1.29–10.6) Prior Venous Thrombosis 13.4% 2.9% 4.6 (1.48–14.5) Infection (prior 2 wks) 32.8% 10.1% 3.2 (1.77–5.9) Medications (prior 12 wks) Antibiotics 31.3% 17.4% 1.8 (1.08–2.99) Clopidogrel 4.5% 0.7% 6.4 (0.65–62.9) Income Level < $25,000 42% 18% 2.3 (1.47–3.6) $25,000 – 70,000 37.3% 52.9% 0.7 (0.49–0.99) > $70,000 11.9% 24.6% 0.5 (0.24–0.98) Characteristics by ADAMTS13 activity ADAMTS13 activity N ADAMTS13 inhibitor (>15 u/ml) ADAMTS13 inhibitor titer (mean) Platelets (mean) Creatinine (mean) Neurologic symptoms Survival Comparison of ADAMTS13 ≤20% vs > 20%, p-values: * 0.0028, † 0.003, ‡ 0.73, # 0.48. < 5% 18 (37.5%) 100% 80.9 22,350 1.4 44% 94% 5–20% 4 (8.3%) 100% 76.4 20,000 1.1 75% 100% > 20% 26 (54.2%) 57.7% 22.5 58,810* 4.3† 58%‡ 89.5%#

Abstract Background : Many idiopathic thrombotic thrombocytopenia purpura (TTP) patients have severe deficiency of ADAMTS13, an enzyme that cleaves ultralarge von Willebrand multimers. We recently reported that thienopyridine-associated TTP is characterized by an immunologic pathway with severe ADAMTS13 deficiency and a non-immunologic pathway with higher ADAMTS13 activity levels. We now compare findings for idiopathic and thienopyridine-associated TTP patients. Methods : Clinical findings and laboratory findings were evaluated for 51 idiopathic and 39 thienopyridine-associated TTP. Results: Clinical findings were similar between idiopathic and thienopyridine-associated TTP for both severe ADAMTS13 deficient and non-deficient patients. Differences were noted in gender and age, relapse rates, and survival. Conclusion : Among TTP patients with ADAMTS13 deficiency, relapses are frequent in idiopathic TTP patients and Rituximab may be useful, while for thienopyridine-associated TTP patients spontaneous relapse are rare as long as no re-exposure occurs. Among ADAMTS13 non-deficient patients, survival is high following therapeutic plasma exchange (TPE) for idiopathic patients but not for thienopyridine-associated TTP patients. Despite similarities, idiopathic and thienopyridine associated TTP probably have different initiating factors. ADAMTS13 activity and clinical characteristics in idiopathic and thienopyridine-associated TTP Idiopathic severe ADAMTS13 deficiency (n=29) †Thienopyridine severe ADAMTS13 deficiency (n=26) Idiopathic non-severe ADAMTS13 deficiency (n=22) †Thienopyridine non-severe ADAMTS13 deficiency (n=13) *p<0.05 for comparison of severe ADAMTS13 deficiency versus non-severe ADAMTS13 deficiency. †Thienopyridine-associated TTP clinical and presenting neutralizing autoantibody data was summarized from the Journal of the American College of Cardiology publication by Bennett et al. in 2007. ‡Thienopyridine-associated TTP remission autoantibody data was summarized Tsai et al, 2002, Bennett et al, 2000, and Orimo et al, 2002, and included 3 patients. §Data from average of ADAMTS13 deficient and non-deficient cohorts. Mean Age 41 67 47 60 Sex (% female) 79% 54% 86% 39% Platelet count/mm3 (mean)* 18,978 9,269 51,409 35,000 Platelet count <20,000/mm3* 69% 96% 23% 38% Hemoglobin (mg/dl; mean) 8.5 8.3 9.0 8.4 Creatinine (mg/dl; mean)* 1.5 2.2 3.2 3.0 Creatinine >2.5 mg/dl* 11% 27% 48% 46% 30-day survival 96% 85% 90% 62% Long-term relapse* 42% 8% 0% 0% Neutralizing autoantibodies to ADAMTS13 (prior to TPE) § 79% 100% 27% 0% Neutralizing autoantibodies to ADAMTS 13 (measured at remission) § 55% 33%‡ 33% 0%

Abstract Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that presents with microangiopathic hemolytic anemia and thrombocytopenia, fevers, renal insufficiency and neurologic features. We reviewed clinical, laboratory, and outcome data for TTP cases with severely deficient versus non-severely deficient ADAMTS13 activity levels. Methods: Mean and median data were from the Surveillance, Epidemiology and Risk Factors for TTP (SERF-TTP) study group for idiopathic TTP cases, the Canadian Apheresis Group (CAG), and five published series (Zheng 2004, Raife 2004, Vesely 2003 (Oklahoma TTP-HUS Registry), Matsumoto 2004 (Japan Referral Center), Bennett 2007). Results: Compared to TTP cases with near-normal ADAMTS13 activity levels (n= 282), TTP cases with severe ADAMTS13-deficiency (n=185) were more likely to have severe thrombocytopenia, normal renal function and neutralizing ADAMTS13 antibodies. Severe ADAMTS13 deficient TTP cases have better overall survival after therapeutic plasma exchange (TPE) but are more likely to relapse. TTP patients with severe ADAMTS13 deficiency were primarily categorized as idiopathic or ticlopidine-associated, while TTP patients with non-severely deficient ADAMTS13 activity levels were frequently categorized as idiopathic, secondary to drugs (clopidogrel, quinine), stem cell transplantation, or cancer. Conclusions: Severe ADAMTS13 deficiency is most commonly idiopathic, has better survival following TPE, and a 35–40% spontaneous relapse rate. By contrast, non-ADAMTS13 deficient TTP cases are usually associated with an underlying disorder or external insults. Amongst this cohort, four series have 47–62% survival rates and three series, which contain mostly idiopathic cases, have 83–90% survival rates following TPE. From this, we propose that TTP may occur by three possible mechanism; ADAMTS13-deficient (antibody-mediated), an immunologic mediated pathway independent of ADAMTS13 (i.e. quinine) that is responsive to TPE, and endothelial injury related TTP that is unresponsive to TPE. Platelet count mean (x10^9/L) Creatinine mean (mg/dl) ADAMTS13 neutralizing antibodies (%) Survival % Relapse % * <15% ADAMTS13 activity cutoff Severe ADAMTS13 Deficiency (<10–15%) SERF-TTP (n=30) 19 1.3 83 97 41 Zheng (n=16) 19 1.6 44 81 38 Bennett (n=26) 15 85 Oklahoma (n=18) 12 1.8 94 81 38 Raife (n=50) * 13 1.2 92 35 Japan (n=34) 35 91 Canada (n=11) 16 2.4 82 Not Severely Deficient ADAMTS13 Activity (> 15%) SERF-TTP (n=22) 57 3.9 35 90 0 Raife (n=57) * 44 2.7 83 9 Canada (n=17) 57 4.1 88 Zheng (n=13) 40 3.0 0 54 Bennett (n=13) 62 Japan (n=66) 9 62 Oklahoma (n=94 ) 23 47 3

Abstract Background: The Surveillance, Epidemiology & Risk Factors for TTP (SERF-TTP) study is the largest prospective cohort of idiopathic TTP cases to date. Methods: Patients with first episode of idiopathic TTP were enrolled at 11 sites in the US. Exclusion criteria include solid organ or allogeneic stem cell transplant, anti-neoplastic therapy or malignancy. All patients underwent therapeutic plasma exchange (TPE). Remission is defined as platelet count >150,000/mm3. ADAMTS13 activity was measured by fluorescence resonance energy transfer assay (FRETS-vWF73, Peptides Int.). ADAMTS13 inhibitor was assessed by ELISA (Technozym ADAMTS13 INH ELISA, Technoclone) and functional inhibition of normal ADAMTS13 activity (modified FRETS). Differences between the groups was evaluated by Chi-square test, t-test or Fisher’s exact test. Results: Complete data is available for 57 cases. 84% were female & median age was 42. ADAMTS13 was severely deficient (<10%) in 53%, moderate (10–50%) in 8%, & normal (>50%) in 39%. Adverse events were frequent & most commonly include citrate toxicity and allergic reactions. Long-term followup was available for 56 patients, and overall relapse rate was 25% with median time to relapse of 11 months. The relapse rate was 41% in patients with severe ADAMST13 deficiency & 0% in patients with normal ADAMTS13 activity (p=0.0077). Conclusions: Severe ADAMTS13 deficiency does not define all cases of idiopathic TTP, yet is associated with a unique syndrome characterized by severe thrombocytopenia, normal renal function, presence of ADAMTS13 neutralizing autoantibodies & high risk of relapse. Non-ADAMTS13 deficient idiopathic TTP has clinical features similar to thrombotic microangiopathies associated with stem cell transplant or drugs such as quinine, yet has a better than expected overall survival after TPE. There is likely an alternate disease mechanism for this cohort, possibly immunologic, which may be responsive to TPE and warrants further study. ADAMTS13 < 10% n=30 ADAMTS13 > 50% n=22 p-value * t-test, ** Fisher’s Exact Test, # Chi-Square Test Presenting Labs Hemoglobin (mean) 8.5 9.2 0.22* Platelet count (mean x10^9/L) 19 57 <0.0005* Serum creatinine (mean) 1.33 3.9 0.0012* ADAMTS13 antibody (neutralizing & non-neutralizing) % 100 63.6 0.0004** ADAMTS13 neutralizing antibody % 83 35 .0003# Presenting Symptoms Neurologic symptoms present 45 52.4 0.23# Diarrhea 23 30.4 0.79# Infection 40 43.5 0.79# Past Medical History Connective Tissue Disease % 10 8.5 0.28# Family history of TTP % 0 4.6 0.11# Remission Labs Hemoglobin (mean) 12.2 8.5 0.16* Platelet count (mean x10^9/L)) 169 152 0.15* Serum creatinine (mean) 1.02 3.7 0.0009* Outcomes Therapy-related Adverse events % 71 55 0.24# Time (days) to remission (plt > 150,000) 9.7 9.2 0.89* Early remission (< 8 days) % 73 57 0.20# 30 day Exacerbation rate % 35 28 0.63# 30 day Survival % 96.6 90.0 0.56** Long-term Relapse % 41 0 0.0077**

Abstract Background: Sickle cell anemia (SCA) is a genetically inherited disorder that can lead to severe sequelae in any organ system. The most clinically devastating complications, e.g. stroke, are managed with chronic red blood cell (RBC) transfusions as curing the underlying SCA is often not an option. Chronic RBC exchange (RBCx), is an effective alternative to simple transfusions and often performed every 4-5 weeks. Isovolemic Hemodilution-Red Blood Cell Exchange (IHD-RBCx) is a modified RBCx method used at UT Southwestern Medical Center (UTSW) and increases the time interval between transfusions, i.e. inter-procedure interval (IPI), up to 9 weeks while maintaining the desired hemoglobin S targets at safe levels. This minimizes the overall lifetime procedures and blood exposures. The standard operating procedure for IHD-RBCx is published (Matevosyan et al, 2012). However, we observed IPI variability between patients in this chronic IHD-RBCx program. We sought to analyze hematologic characteristics in a cohort of adult SCA patients that may be associated with this noted variability. Methods: This IRB approved cross-sectional study evaluated medical and blood bank records of adult patients with SCA, i.e. hemoglobin SS or Sβ0 thalassemia genotypes, undergoing chronic IHD-RBCx at UTSW adult hospital sites between January 1, 2012 and December 31, 2013. Excluded participants were those with autoimmune disease, non-compliance with IHD-RBCx leading to delays > 7 days, or use of hydroxyurea or steroids within four months of the study period. Patients with < 5 exchanges were excluded as several procedures are needed to determine baseline IPIs. The primary indication for IHD-RBCx was secondary stroke prevention. Three subjects had alternative indications (i.e. recurrent severe acute chest syndrome that failed hydroxyurea therapy, intractable pain and severe anemia ineligible for iron chelation due to end-stage renal disease). Median values during the 2 year study were determined for the IPI, laboratory, and RBC properties for use in subsequent analyses. Correlation and multiple regression analyses were performed to determine variables predictive of IPI. Results: Twenty-four SCA patients in this chronic IHD-RBCx transfusion program met inclusion criteria of which 14 (58.3%) were female with age range 18-41 years. Three subjects had incomplete data. The median number of packed RBC (pRBC) units per IHD-RBCx was 8 (range: 6-11 units). The median volume per unit of pRBCs was 304.5 mL (range: 298.8-326.5 mL) with average age of the pRBCs 5.8 days ± 0.7 days. The median IPI was 55.8 days (range: 36.0-65.5 days). The strongest correlation with IPI was the change from the mid to post-procedure hemoglobin and hematocrit values, r=0.56, p=0.005 and r=0.57, p=0.003, respectively. Participants with documented direct antiglobulin test positivity (n=7), compared to those who remained negative (n=16), had 4.9 days increased IPI. This difference was not statistically significant, p=0.19. ABO differences in blood type also did not show statistical significant differences. However, A+ subjects had a 58 day interval compared to 51, 52, 53 days for B+, O+, O- respectively (Figure). In multiple regression models, log blood urea nitrogen (BUN) and post-procedure white blood cell count (WBC) were found to be independent predictors of IPI, beta=-11.3, p=0.04 and -2.1, p=0.03 respectively, with adjusted R2=0.31. Conclusions: Chronic IHD-RBCx effectively treats severe SCA complications. Discontinuing transfusions lead to repeat stroke events or the recurrence of disease manifestations making chronic transfusion programs an indefinite therapy. Outside of the expected correlation between the IPI and hemoglobin/hematocrit, WBC and BUN were found to have negative associations with IPIs. The decrease in WBCs is likely due to the direct clearing effect by the operating system. The association between BUN and IPI may imply relationship with renal function. Interestingly, association with creatinine was not statistically significant. The study is limited by the small sample size. Future studies of similar cohorts should prospectively evaluate target mechanisms which may lead to interventions that can minimize lifetime blood exposures given the growing demands for continued RBCx in severe SCA. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.