In the absence of head-to-head trials of chimeric antigen receptor T-cell therapies, a matching-adjusted indirect comparison (MAIC) evaluated the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) as second-line (2L) therapies in patients with early relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Data sources were the pivotal phase 3 trials: individual patient-level data from TRANSFORM [liso-cel (NCT03575351), N = 184] and summary-level data from ZUMA-7 [axi-cel (NCT03391466), N = 359]. Efficacy analyses were anchored via the common standard-of-care comparator arms and showed no statistically significant differences. Safety analyses were unanchored, showing liso-cel had lower odds (95% confidence interval) of grade ≥3 serious treatment-emergent adverse events [0.49 (0.27-0.90)], cytokine release syndrome [any grade, 0.09 (0.04-0.18); grade ≥3, 0.09 (0.01-0.75)], and neurological events [any grade, 0.08 (0.03-0.18); grade ≥3, 0.21 (0.06-0.68)]. In this MAIC, liso-cel demonstrated comparable efficacy and a more favorable safety profile versus axi-cel for 2L treatment of R/R LBCL.

The treatment landscape for relapsed or refractory (R/R) follicular lymphoma (FL) has changed with the introduction of anti-CD19 chimeric antigen receptor T-cell therapies, including lisocabtagene maraleucel (liso-cel) and CD20 × CD3 bispecific T-cell–engaging monoclonal antibodies such as mosunetuzumab. Liso-cel and mosunetuzumab have demonstrated positive benefit-risk profiles for third-line or later (3L+) treatment of patients with R/R FL and are approved treatments for these patients. In the absence of a prospective, randomized study, we conducted an unanchored matching-adjusted indirect comparison (MAIC) to assess the efficacy and safety of liso-cel and mosunetuzumab for 3L+ treatment in patients with R/R FL. Unanchored MAICs were performed to estimate relative treatment effects between TRANSCEND FL (NCT04245839) and GO29781 (NCT02500407). For TRANSCEND FL, the leukapheresis set (N = 114) was used for primary comparisons of the following efficacy endpoints: objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS). The treated set (N = 107) was used for comparisons of the following safety endpoints: cytokine release syndrome (CRS), neurological events (NE), serious infections, and use of corticosteroids or tocilizumab for CRS. Sensitivity analyses were conducted for efficacy using the TRANSCEND FL treated efficacy set (N = 101). After adjustment, liso-cel was associated with higher ORR (odds ratio [OR] = 3.78, 95

Background: Two CAR T cell therapies, liso-cel and axi-cel, demonstrated superior efficacy over salvage chemotherapy and autologous transplant as 2L therapy in transplant-intended pts with high-risk R/R LBCL, yet no head-to-head comparisons have been performed. A previous MAIC in the 2L setting with a median follow-up of 17.5 mo for liso-cel and 24.9 mo for axi-cel showed comparable efficacy and more favorable safety outcomes for liso-cel with lower rates of all-grade and grade ≥ 3 cytokine release syndrome (CRS) and neurological events (NEs) (Abramson JS, et al. Blood 2022). Here, we present updated results with long-term follow-up for liso-cel and axi-cel. Methods: MAICs were used to estimate population-adjusted relative treatment effects associated with liso-cel for event-free survival (EFS), PFS, ORR, and CR rate (TRANSFORM; NCT03575351; N = 184; data cutoff date: October 2023) vs axi-cel (ZUMA-7; NCT03391466; N = 359; data cutoff date: January 2023) and safety (TRANSFORM, n = 183; ZUMA-7, n = 338). Pts were excluded from the TRANSFORM data set if they did not meet ZUMA-7 eligibility criteria (ie, matching). Individual pt data (IPD) for pts remaining in the TRANSFORM data set were weighted using a method-of-moments propensity score model to match the marginal distribution (ie, mean, variance) of clinical factors among pts from ZUMA-7 (ie, adjustment). Baseline characteristics and outcome measures were revised to align with those defined in ZUMA-7. Efficacy comparisons were anchored through the common comparator, standard of care (SOC; with similar protocol-defined salvage chemotherapy regimens in both trials, followed by high-dose chemotherapy and autologous transplant in responders). Hazard ratios (HRs) were used to compare time-to-event outcomes (EFS, PFS), and odds ratios were used to compare binary outcomes (ORR, CR rate, safety). Selection and rank ordering of the treatment effect modifiers were guided by analysis of the TRANSFORM IPD and clinical experts. Factors to match (ie, pts from TRANSFORM were removed) and adjust (ie, pts from TRANSFORM were reweighted) for efficacy and safety comparisons were reported previously (Abramson JS, et al. Blood 2022). Safety comparisons were unanchored due to the absence of CAR T cell-associated toxicities in the SOC arms. Bridging chemotherapy was allowed in TRANSFORM but not in ZUMA-7; it was not possible to adjust for this factor given sample size constraints. Results: Median study follow-up time was 33.9 mo for liso-cel and 47.2 mo for axi-cel. Efficacy outcomes were comparable between therapies in the unmatched/unadjusted comparison. For liso-cel vs axi-cel, respectively, median (95% CI) EFS was 29.5 mo (9.5‒not reached [NR]) vs 8.3 mo (4.5‒15.8) with HR (95% CI) of 0.94 (0.60‒1.46), and median (95% CI) PFS was 29.5 mo (10.3‒NR) vs 14.7 mo (5.4‒43.5) with HR of 0.90 (95% CI, 0.56‒1.47). Median ORR was 87% vs 83% with odds ratio (95% CI) of 1.41 (0.58‒3.40), and CR rate was 74% vs 65% with odds ratio (95% CI) of 0.95 (0.44‒2.03). After matching with ZUMA-7 for pt eligibility, the TRANSFORM sample size was 158; matching and adjusting for the selected effect modifiers resulted in an effective sample size of 80 for the primary efficacy scenario comparisons (sample size for ZUMA-7 and median efficacy values for axi-cel were unchanged). After matching and adjustment, efficacy outcomes remained comparable between therapies. Median (95% CI) EFS for liso-cel was NR (6.21‒NR) with HR (95% CI) of 0.75 (0.43‒1.33), and median (95% CI) PFS was NR (9.4-NR) with HR (95% CI) of 0.68 (0.37‒1.23). ORR was 85% with odds ratio (95% CI) of 1.63 (0.60‒4.44), and CR rate was 68% with odds ratio (95% CI) of 0.94 (0.40‒2.22). For safety, MAIC results demonstrated lower odds ratios (95% CI) of grade ≥ 3 serious treatment-emergent adverse events (TEAEs; 0.49 [0.27‒0.90]), CRS (any grade, 0.09 [0.04‒0.18]; grade ≥ 3, 0.09 [0.01‒0.75]), and NEs (any grade, 0.08 [0.03‒0.18]; grade ≥ 3, 0.21 [0.06‒0.68]) for liso-cel vs axi-cel. Conclusions: Results from this updated MAIC of liso-cel and axi-cel for the 2L treatment of R/R LBCL showed comparable efficacy, with more favorable safety outcomes for liso-cel. Liso-cel demonstrated a better safety profile with lower rates of grade ≥ 3 serious TEAEs and lower rates of all-grade and grade ≥ 3 CRS and NEs compared with axi-cel.

INTRODUCTION:Etranacogene dezaparvovec gene therapy for haemophilia B demonstrated superior efficacy at 24 months in reducing bleeds versus a ≥6-month lead-in period of prophylaxis with FIX products in the phase 3 trial, HOPE-B. In the absence of head-to-head comparisons of etranacogene dezaparvovec versus FIX products, indirect treatment comparisons (ITC) can be used.AIM:To compare the efficacy of etranacogene dezaparvovec versus rIX-FP, rFIXFc and N9-GP using ITC, and support HOPE-B results.METHODS:Data were leveraged from Phase 3 pivotal trials: HOPE-B, PROLONG-9FP, B-LONG and Paradigm 2. Annualised bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds, and FIX consumption were assessed using inverse probability of treatment weighting and matching adjusted indirect comparisons.RESULTS:Etranacogene dezaparvovec demonstrated statistically significantly lower bleeding rates versus all comparators. Rate ratios for ABR, AsBR and AjBR versus rIX-FP were 0.19 (p < .0001), 0.08 (p < .0001) and 0.09 (p < .0001), respectively. Rate ratios for ABR, AsBR and AjBR versus rFIXFc were 0.14 (p < .0001), 0.13 (p = .0083) and 0.15 (p = .0111), respectively. Rate ratios for ABR and AsBR, versus N9-GP were 0.24 (p = .0231) and 0.13 (p = .0071), respectively. Etranacogene dezaparvovec demonstrated significantly higher percentage of patients with no bleeds versus rIX-FP and rFIXFc; odds ratios: 17.60 (p < .0001) and 5.65 (p = .0037), respectively. Etranacogene dezaparvovec resulted in significantly lower FIX consumption than all comparators.CONCLUSIONS:ITC suggests that etranacogene dezaparvovec offers patients with haemophilia B (≤2% of normal FIX expression) a single dose treatment that can significantly reduce bleeding rates and eliminate routine infusions associated with FIX therapies.

Background:The tx landscape of R/R FL is evolving with the availability of anti-CD19 chimeric antigen receptor (CAR) T cell therapies and CD20xCD3 bispecific T-cell-engaging monoclonal antibodies (mAb). Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell therapy which recently reported a positive benefit-risk tx profile for the 3L+ tx of patients with R/R FL (Morschhauser F, et al. ICML 2023; LBA4). Mosunetuzumab, a CD20xCD3 bispecific T-cell-engaging mAb, is approved for the tx of R/R FL after 2 or more lines of therapy (LOT). In the absence of head-to-head data, we conducted an unanchored MAIC to compare the efficacy and safety of liso-cel and mosunetuzumab for the 3L+ tx of patients with R/R FL. Methods: Unanchored MAICs were used to estimate population-adjusted relative tx effects between individual patient-level data from TRANSCEND FL (NCT04245839; data as of January 27, 2023; median follow-up of 19.3 months) and aggregate data from GO29781 (NCT02500407; data as of August 27, 2021; median follow-up of 18.3 months; N = 90). For TRANSCEND FL, the leukapheresed (intention to treat [ITT]) set (N = 114) was used for primary comparisons of efficacy endpoints: Progression-free survival (PFS), objective response rate, and complete response rate (all per independent review committee assessment). Overall survival was not analyzed due to the low rate of events. The treated efficacy set (n = 101) was used for a sensitivity analysis of efficacy comparisons. The treated set (n = 107) was used for comparisons of safety endpoints: cytokine release syndrome (CRS), neurological events (NEs), serious infections, and use of corticosteroids or tocilizumab for CRS. Baseline characteristics and outcome measures in TRANSCEND FL were redefined to align with those reported in GO29781. Data from TRANSCEND FL were weighted using a method-of-moments propensity score model to match the marginal distribution (ie, mean, variance) of clinical factors among patients from GO29781. A panel of expert clinicians selected and ranked tx effect modifiers separately for efficacy and safety endpoints. For efficacy, factors adjusted for included number of prior systemic LOTs, progression of disease ≤ 24 months from initiation of immunochemotherapy, bulky disease at screening, FL International Prognostic Index risk factor, refractory to last therapy, double refractory to an anti-CD20 antibody and alkylating agent, ECOG PS at screening, sex, and prior autologous HSCT. For safety, factors adjusted for included age, bulky disease at screening, refractory to last therapy, number of prior systemic LOTs, ECOG PS at screening, Ann Arbor stage, and sex. Hazard ratios (HR) were used to compare PFS, and odds ratios (OR) were used for response rates and safety outcomes. Results: After adjusting for all available factors, when compared with mosunetuzumab, liso-cel was associated with higher objective response rate (OR, 3.78 [95% CI, 1.48‒9.67]), and complete response rate (OR, 6.46 [2.85‒14.65]), and improved PFS (HR, 0.28 [0.16‒0.49]) based on an effective sample size (ESS) of 71.4 (Figure). Results were consistent across all scenario analyses, including unadjusted comparisons and sensitivity analyses using the treated efficacy set for TRANSCEND FL. Although liso-cel was associated with higher incidence of any-grade CRS (OR, 1.86 [1.01‒3.43]) and any-grade NEs (OR, 2.16 [0.72‒6.44]), it demonstrated a lower incidence of grade ≥ 3 CRS (OR, 0.45 [0.04‒5.13]) and grade 3-4 serious infections (OR, 0.35 [0.12‒1.03]) based on an ESS of 81.9 compared with mosunetuzumab. Furthermore, liso-cel was associated with reduced use of corticosteroids for CRS management (OR, 0.14 [0.03‒0.65]), while the use of tocilizumab was higher in patients treated with liso-cel (OR, 2.27 [0.86‒5.99]). Conclusions: In this MAIC, liso-cel was associated with improved efficacy compared with mosunetuzumab. Liso-cel had a lower incidence of grade ≥ 3 CRS, grade 3-4 serious infections, and steroid use for management of CRS; however, liso-cel exhibited higher incidence of any-grade CRS, any-grade NEs, and tocilizumab use for CRS management. Safety comparisons were confounded by preventative use of corticosteroids in all patients in GO29781 and definition differences, most notably for NEs. These findings highlight a potential positive benefit-risk profile of liso-cel over mosunetuzumab as a 3L+ tx option for R/R FL.

Background: Two chimeric antigen receptor (CAR) T cell therapies, liso-cel and axi-cel, demonstrated superior efficacy over salvage chemotherapy and autologous transplant for chemotherapy sensitive disease as 2L therapy in transplant-intended pts with high-risk R/R LBCL, yet no head-to-head clinical trials have compared CAR T cell therapies. A previous MAIC report showed comparable efficacy and an improved safety profile of liso-cel vs axi-cel in 3L+ R/R LBCL (Maloney et al. J Hematol Oncol 2021). Here we conducted a MAIC of treatment effects in the 2L setting for liso-cel vs axi-cel in pts with R/R LBCL. Methods: MAICs were used to estimate population-adjusted relative treatment effects associated with liso-cel for event-free survival (EFS), PFS, ORR, and CR rate (TRANSFORM; NCT03575351; N = 184) vs axi-cel (ZUMA-7; NCT03391466; N = 359), as well as safety (TRANSFORM, N = 183; ZUMA-7, N = 338). Pts from TRANSFORM were excluded from this analysis if they did not satisfy eligibility criteria specified in ZUMA-7 (ie, matching). Individual pt data (IPD) for pts who remained in the TRANSFORM data set were weighted using a method-of-moments propensity score model to match the marginal distribution (ie, mean, variance) of clinical factors among pts from ZUMA-7 (ie, adjustment). Baseline characteristics and outcome measures were revised to align with those defined in ZUMA-7. Efficacy comparisons were anchored through the common comparator, standard-of-care (SOC; with similar protocol-defined salvage chemotherapy regimens in both trials, followed by high-dose chemotherapy and autologous transplant in responders). Hazard ratios (HRs) were used to compare time to event outcomes (EFS, PFS), and odds ratios (OR) were used to compare binary outcomes (ORR, CR rate, safety). Selection and rank-ordering of the treatment effect modifiers were guided by analysis of the TRANSFORM IPD and by a panel of expert clinicians. Factors to match (ie, pts from TRANSFORM were removed) and adjust (ie, pts from TRANSFORM were re-weighted) for efficacy included: central nervous system involvement, absolute lymphocyte count at screening, age, sex, geographic region, secondary age-adjusted International Prognostic Index (sAAIPI) score, sum of the product of perpendicular diameters at baseline, R/R status to 1L therapy, double/triple-hit status, and disease histology. Safety comparisons were unanchored, owing to the absence of CAR T cell-associated toxicities in the SOC arms; factors for safety MAIC included: LVEF < 50% and bilirubin > 1.5 mg/dL at screening, age, and sAAIPI score. Notably, bridging chemotherapy was allowed in TRANSFORM but not in ZUMA-7; it was not practically possible to adjust for this factor given sample size constraints. Results: Unmatched and unadjusted comparisons showed no differences in median (95% CI) EFS for liso-cel (10.1 mo [6.1‒not reached]) vs axi-cel (8.3 mo [4.5‒15.8]; HR, 0.94 [0.58‒1.52]). After matching with ZUMA-7 for pt eligibility, the TRANSFORM sample size was 157; matching and adjusting for the selected effect modifiers resulted in an effective sample size of 69 for the primary efficacy scenario comparisons (sample size unchanged for ZUMA-7). MAIC primary scenario efficacy results for these populations showed no differences (Table). Median (95% CI) EFS after matching and adjustment was 9.5 mo (5.95‒not reached) for liso-cel. Results were consistent for other efficacy parameters of PFS, ORR, and CR rate. Sensitivity scenario comparisons that included additional adjustment factors led to similar results. MAIC safety results demonstrated lower odds of key CAR T cell-associated AEs with liso-cel vs axi-cel: cytokine release syndrome (CRS) any grade (OR, 0.09 [95% CI: 0.04‒0.19]), CRS grade ≥ 3 (OR, 0.10 [0.01‒0.81]), neurological events (NE) any grade (OR, 0.10 [0.04‒0.22]), and NEs grade ≥ 3 (OR, 0.21 [0.06‒0.69]). Conclusions: Findings from this comparative analysis of liso-cel and axi-cel for the 2L treatment of R/R LBCL show comparable efficacy of liso-cel and axi-cel, with more favorable safety outcomes for liso-cel where lower rates of all-grade and grade ≥ 3 CRS and NEs were observed. These results indicate liso-cel may have a better safety profile than axi-cel in 2L+ R/R LBCL and are consistent with those from the 3L+ MAIC analysis. This MAIC will be updated with the TRANSFORM primary analysis dataset when available. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract Background There are no head-to-head clinical studies comparing chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed or refractory aggressive large B-cell lymphomas. Naive, indirect comparisons may be inappropriate, as the study designs and patient populations could differ substantially. Matching-adjusted indirect comparisons (MAIC) can reduce many biases associated with indirect comparisons between studies. To determine the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) to tisagenlecleucel, we describe an unanchored MAIC of the pivotal studies TRANSCEND NHL 001 (TRANSCEND; NCT02631044; liso-cel) and JULIET (NCT02445248; tisagenlecleucel). Methods Individual patient data (IPD) from TRANSCEND were available to the authors; for the JULIET pivotal study, summary-level data from the published study were used. To balance the populations between two studies, IPD from TRANSCEND were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors among patients from JULIET. Results Results from the primary MAIC showed liso-cel had statistically significant greater efficacy than tisagenlecleucel (objective response rate: odds ratio [OR] = 2.78, 95% confidence interval [CI]: 1.63‒4.74; complete response rate: OR = 2.01, 95% CI: 1.22‒3.30; progression-free survival: hazard ratio [HR] = 0.65, 95% CI: 0.47‒0.91; overall survival: HR = 0.67, 95% CI: 0.47‒0.95). MAIC of safety outcomes showed lower ORs for all-grade and grade ≥ 3 cytokine release syndrome, and grade ≥ 3 prolonged cytopenia for liso-cel when compared with tisagenlecleucel; there were no statistically significant differences detected for other safety outcomes. Conclusions Overall, this MAIC of two CAR T-cell therapies indicates liso-cel had favorable efficacy and a comparable or better safety profile relative to tisagenlecleucel. Clinical trial registration: ClinicalTrials.gov identifiers: NCT02631044 and NCT02445248.

ABSTRACT Background: Lumbar total disc replacement (TDR) has produced results similar or superior to fusion in treating symptomatic disc degeneration. Some patients have reported onset of leg pain early after surgery. Little information is available specifically on this problem. The purpose of this study was to investigate the incidence of early-onset postoperative leg pain following lumbar TDR and to describe strategies for its treatment. Methods: The study was based on a post hoc analysis of prospectively collected adverse event data from 283 patients in the activL Food and Drug Administration investigational device exemption study. Early-onset leg pain was defined as occurring between 0 and 4 weeks postprocedure, and the baseline visual analog scale score in the affected leg(s) was <25 (of 100). The treatment types these patients received were analyzed. Results: Among 283 patients, 26 (9.2%) had an early-onset leg pain event. The majority of these events resolved (20/26, 76.9%). Of those resolving, 55% (11/20) did so within 3 months. Most patients received at least 1 drug treatment for leg pain (92.3%). Of those receiving drug therapy, the most common type was neurogenic (61.5%), followed by narcotics (46.2%). Steroid use was prescribed in 30.8%. The majority of resolved cases were not on narcotics and resolved with neurogenic drugs. Three patients went on to have surgery, none of whom benefited from it. Age, body mass index, and baseline disability scores were predictive of time to resolution. Conclusion: Early-onset postoperative leg pain occurred in approximately 10% of lumbar TDR patients. The majority of events resolved, often within 3 months. Treatment with conservative care, including medication(s), was more effective in resolving symptoms rather than surgery. Clinical Relevance: This study provides useful information for providers and patients on the incidence, treatment, and resolution of leg pain with onset after lumbar TDR and not related to direct neural compression identified by imaging. Level of Evidence: 2.

Abstract Background In the absence of randomized studies directly comparing chimeric antigen receptor T cell therapies, this study used matching-adjusted indirect comparisons (MAIC) to evaluate the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) in patients with relapsed or refractory large B cell lymphoma (LBCL). Methods Primary data sources included individual patient data from the TRANSCEND NHL 001 study (TRANSCEND [NCT02631044]; N = 256 for efficacy set, N = 269 for safety set) for liso-cel and summary-level data from the ZUMA-1 study (NCT02348216; N = 101 for efficacy set, N = 108 for safety set) for axi-cel. Inter-study differences in design, eligibility criteria, baseline characteristics, and outcomes were assessed and aligned to the extent feasible. Clinically relevant prognostic factors were adjusted in a stepwise fashion by ranked order. Since bridging therapy was allowed in TRANSCEND but not ZUMA-1, the initial efficacy and safety analyses included bridging therapy use as a matching factor (TRANSCEND patients who received bridging therapy were removed). Subsequent sensitivity analyses excluded this matching factor. Results The initial analysis showed similar MAIC-weighted efficacy outcomes between TRANSCEND and ZUMA-1 for overall and complete response rates (odds ratio [95% confidence interval (CI)], 1.40 [0.56–3.49] and 1.21 [0.56–2.64], respectively) and for overall survival and progression-free survival (hazard ratio [95% CI], 0.81 [0.44–1.49] and 0.95 [0.58–1.57], respectively). MAIC-weighted safety outcomes favored liso-cel, with significantly lower odds of all-grade and grade ≥ 3 cytokine release syndrome (odds ratio [95% CI], 0.03 [0.01–0.07] and 0.08 [0.01–0.67], respectively) and study-specific neurological events (0.16 [0.08–0.33] and 0.05 [0.02–0.15], respectively). Efficacy and safety outcomes remained similar in sensitivity analyses, which did not include use of bridging therapy as a matching factor. Conclusions After matching and adjusting for clinically relevant prognostic factors, liso-cel demonstrated comparable efficacy and a more favorable safety profile compared with axi-cel in patients with third- or later-line relapsed or refractory LBCL. Trial registration: NCT02631044 and NCT02348216

OBJECTIVES: Vaso-occlusion is a hallmark feature of sickle cell disease (SCD) that promotes ischemia-reperfusion injury and leads to acute pain episodes, known as vaso-occlusive crises (VOCs). VOCs are disabling and frequently impact on the ability of the patient to attend work or school and participate in activities of daily living. VOCs are the primary reason for medical facility visits amongst SCD patients and are associated with increased morbidity and mortality. The acute pain of a VOC often requires parenteral opioid administration in hospital emergency departments and inpatient units. Patients are also frequently prescribed oral opioids to aid in home management of VOCs. The development of new SCD therapies that have been shown to reduce or prevent VOCs has generated interest in their potential as opioid sparing agents. This study evaluated the effect of crizanlizumab-a humanized monoclonal antibody indicated in the US for reduction of VOCs in SCD-on opioid use for managing VOC related pain. METHODS: In this post hoc analysis, subject-level data from the SUSTAIN (NCT01895361) trial were analyzed to determine the number of days of opioid use by patients in both the 5.0 mg/kg crizanlizumab and placebo arms during the 52-week follow-up period. Opioid use captured in case report forms was retrospectively assessed. Due to the common use of "as needed" (PRN) dosing for analgesics, a decision tree was developed in conjunction with clinical advice to guide classification of the opioid as being taken or not taken on a given day based on clinically plausible assumptions. Assumptions considered dose frequency (fixed vs. PRN), route of administration (parenteral vs. oral), and concomitant medications (anti-emetics and anti-histamines). Opioid record start dates, end dates, and dose frequencies were used to determine the number of unique days during the trial that each patient had taken at least one opioid. The annualized days with opioid use was calculated for each patient by dividing their number of unique days on opioids by their duration (days) in the trial. The distribution of annualized days with opioid use was compared between patients from the 5.0 mg/kg crizanlizumab and placebo arms. Mann-Whitney U tests with p-values were used to test differences between arms. A four-step analysis was planned to incorporate an increasing number of assumptions to define whether the opioid had been taken on a given day (see footnote of Table 1). Analyses were performed primarily in the per-protocol (PP) population considering all routes of administration and parenteral use only. Outcomes in the intention-to-treat (ITT) population were also assessed. RESULTS: The PP population included 40 patients in the 5.0 mg/kg crizanlizumab arm and 41 patients in the placebo arm. A comparison of the baseline demographics (age, sex, genotype, hydroxyurea use, crisis frequency, and opioid use) showed no statistically significant differences between the two arms. Results of the final step of each analysis are presented as the primary analysis (see Table 1); results of Step 1 were considered a sensitivity analysis (not shown). The median annualized days with opioid use in the PP population was lower in the crizanlizumab arm compared with the placebo arm (absolute reduction: 4.00 days; relative reduction: 57%; p=0.162). The median annualized days with parenteral opioid use was lower in the crizanlizumab arm compared with the placebo arm (absolute reduction: 2.01; relative reduction: 50%; p=0.047). Results in the ITT population (see Table 1) and for sensitivity analyses (not shown) showed similar trends of reduced annualized days with opioid use for patients in the crizanlizumab group compared to the placebo group. CONCLUSIONS: These findings indicate that crizanlizumab, compared with placebo, may reduce the annual number of days where opioids are used to manage pain from VOCs. Importantly, the benefit was observed for parenteral and oral opioids, demonstrating clinical and patient relevance. These findings are concordant with the tendency for crizanlizumab to reduce the number of VOCs experienced by SCD patients annually; the primary finding of the SUSTAIN trial. The reduction in opioid use with crizanlizumab requires exploration in future studies, but the findings of this study translate into positive clinical and patient-relevant outcomes beyond reducing the frequency of VOCs. Disclosures Smith: Shire: Research Funding; Imara: Research Funding; Novo Nordisk: Consultancy; Ironwood: Consultancy; Pfizer: Consultancy; Incyte: Other: Investigator; Health Resources and Services Administration: Other: Investigator, Research Funding; Patient-Centered Outcomes Research Institute: Other: Investigator, Research Funding; NHLBI: Research Funding; Shire, Inc.: Other: Investigator, Research Funding; Global Blood Therapeutics, Inc.: Consultancy, Research Funding; Novartis, Inc.: Consultancy, Other: Investigator, Research Funding; Emmaeus Pharmaceuticals, Inc.: Consultancy; GlycoMimetics, Inc.: Consultancy. Ataga:Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Research Funding; Editas Medicine: Honoraria; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Forma Therapeutics: Consultancy; Modus Therapeutics: Honoraria; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding. Saraf:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Boards, Speakers Bureau; Novartis, Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer, Global Blood Therapeutics, Novartis: Research Funding. Adisa:Novartis Pharmaceuticals Corporation: Current Employment. Bailey:Novartis Pharmaceuticals Corporation: Current Employment. Ramscar:Novartis Pharma AG: Current Employment. Bonner:Eversana: Current Employment. Brown:Eversana: Current Employment. Pastor:Eversana: Current Employment.

Background: Sickle Cell Disease (SCD) describes a group of inherited hemolytic disorders caused by structurally abnormal variants of hemoglobin, which result in the sickle-shaped red blood cells (RBCs) that are characteristic of the disease. In patients with SCD, overexpression of adhesion molecules such as P-selectin bind sickled RBCs to endothelial cells; this contributes to hemolytic anemia and vaso-occlusive crises (VOCs), which are associated with severe acute and chronic pain. Patients with sickle cell disease often experience disease-related complications, affecting a diverse range of organs, thought to be due to the systemic impact of chronically inflamed vasculature, ongoing hemolysis and ischemic damage as a result of vaso-occlusive events. Many of these SCD-related complications are associated with significant morbidity and poor quality of life. The relationship between VOC frequency and the incidence of these complications is still being assessed. This study aimed to assess the relationship between the number of VOC experienced in the previous year and the occurrence of complications using real world evidence from the UK, specifically the Hospital Episode Statistics (HES) database. OBJECTIVE: To examine the relationship between the number of VOCs reported in the previous 12 months and the presence of SCD-related complications using a mixed modelling approach. METHODS: All patients reported with a diagnosis of SCD between 2008 and 2017 in the NHS England's HES database were identified. Detailed follow-up data on the number of vaso-occlusive crisis events and occurrence of complications was evaluated using ICD-10 diagnosis codes. Assuming no unmeasured confounding, the causal effect of VOCs, categorized into 3 groups (0, 1-2, 3+), was estimated using marginal structural models (MSM) for the complications reported in the dataset. To obtain inverse probability of treatment and censoring weights (IPTW and IPCW), the probability of being in each VOC category was estimated with a multinomial logistic model, and subsequently, the probability of being censored was estimated with a binary logistic model. The two models were adjusted for age, gender, ethnicity, and the occurrence in the previous 12 months of the 20 most common SCD complications and comorbidities in the dataset. Pooled logistic regressions were used to approximate the IPW-MSM Cox model. E-values were used to assess the minimum strength of association that an unmeasured confounder would have to have with both exposure (VOC) and outcome in order to fully explain away the observed relationship. Uncertainty in the magnitude of the E-value required to explain observed associations was explored by calculating values for both the point estimate and the lower bound of the confidence interval. RESULTS: A total of 15,076 patients were identified with a diagnosis of SCD in the HES database for this analysis. Patients had a median age of 30 and a female-male ratio of 1.7:1. A broad range of SCD related-complications were experienced by patients in the UK as shown in Table 1. Rates of some complications were observed less frequently than expected, in particular, leg ulcers, pulmonary hypertension, osteomyelitis, priapism and acute kidney injury, reported at <5% (Table 1). The hazard ratio associated with experiencing 3+VOCs versus 0 VOC in the previous year was calculated for all identified complications, resulting in a HR ≥5, for: priapism, osteomyelitis and acute chest syndrome; HR ≥2 to <5 for: gall stones, avascular necrosis, sepsis, cardiomegaly, pulmonary hypertension, CNS complications, leg ulcers, cellulitis, hyposplenism, liver complications and acute kidney injury. E-values (Table 1) suggest that most outcomes are robust to considerable unmeasured confounding, although large confidence intervals resulted in small lower-bound E-values for some outcomes (e.g. leg ulcers: 3.62 lower-bound: 1.00). Large E-values (>= 3 based on similar research in SCD) suggest results are robust to considerable unmeasured confounding, while small values imply greater fragility. CONCLUSIONS: This analysis shows that vaso-occlusive crises are related to the occurrence of important complications of sickle cell disease. Reducing the annual incidence of VOC may significantly lessen the ongoing organ damage and morbidity but may also improve the patient's quality of life with respect to these conditions. Disclosures Bailey: Novartis: Employment. Abioye:Novartis: Employment. Morgan:HCD Economics: Employment. Burke:HCD Economics: Employment. Disher:Cornerstone Research Group: Employment. Brown:Cornerstone Research Group: Employment. Bonner:Cornerstone Research Group: Employment. Herquelot:HEVA: Employment. Lamarsalle:HEVA: Employment. Raguideau:HEVA: Employment.