Haptoglobin 1-1 Isoform Predicts Higher Serum Haptoglobin Concentration and Lower Multiorgan Failure Risk in Sickle Cell Disease

Abstract Haptoglobin (HP) is the major scavenger of cell-free hemoglobin in circulation. When haptoglobin is depleted, cell-free hemoglobin can lead to organ damage through direct oxidative injury, upregulation of inflammatory pathways, and depletion of nitric oxide. A common polymorphism in HP gives rise to structurally and functionally distinct phenotypes: HP 1-1, HP 2-1, and HP 2-2. In people of African descent, the HP 1-1 and 2-1 phenotypes have been associated with higher serum HP concentrations compared to the HP 2-2 phenotype (PMID 10807979). In hemolytic diseases, such as sickle cell disease (SCD), the consequence of the HP polymorphism is unclear but could influence cell-free hemoglobin processing and susceptibility to organ damage. We first investigated whether the HP isoforms are associated with HP concentrations at steady-state. Between 10/2009 and 6/2018, we recruited 431 SCD patients into a longitudinal registry at our institution during a routine clinic visit, which we defined as steady-state. Baseline clinical and laboratory data were collected at the time of enrolment. The median age of the cohort was 32 (interquartile range [IQR], 24 - 43) years, 43% were male, 76% were SCD SS or Sβ 0-thalassemia genotype, and 46% were on hydroxyurea at the time of enrolment. Genotyping of the HP polymorphisms by PCR demonstrated the HP 1-1 isoform in 30% (n = 129), the HP 2-1 isoform in 47% (n = 203), and the HP 2-2 isoform in 23% (n = 99) of the SCD cohort. Serum samples were available in 244 of the 431 SCD patients at steady-state. Serum concentrations of HP, measured by ELISA, were higher in those with the HP 1-1 isoform compared to the HP 2-1 or 2-2 isoform (Figure). In a linear regression model, independent variables associated with steady-state serum HP concentration included SCD SS or Sβ 0-thalassemia genotype (β -1.8; 95% CI: -2.5 to -1.0; P < 0.001), LDH (natural log β -0.9; 95% CI: -0.2 to -1.6; P = 0.018), hydroxyurea use (β 0.6; 95% CI: 0.1 to 1.1; P = 0.02), and HP 1-1 isoform (β 0.5, 95% CI: 0 to 1.1; P = 0.049), adjusting for age and sex. Between 9/2020 and 5/2021, we collected an additional 38 serum samples from SCD patients during a hospitalization for vaso-occlusive crisis (VOC) and serum samples from 7 SCD patients during a hospitalization for acute chest syndrome. The HP 1-1 isoform was associated with higher serum HP concentrations during VOC and during acute chest syndrome compared to the HP 2-1 or 2-2 isoforms (Figure). Interestingly, the serum HP trended higher from steady-state to VOC and to acute chest syndrome in SCD patients with the HP 1-1 isoform (β +1.1, P = 0.085) but trended lower in those with the HP 2-1 or 2-2 isoform (β -0.5, P = 0.099). Next we tested whether the HP 1-1 isoform is protective against multi-organ failure during hospitalizations for acute chest syndrome. For the longitudinal analysis, we focused on SCD patients with > 6 months of follow up at our institution (n = 391). A multiorgan failure event was defined as organ dysfunction involving at least 2 of the following organ systems: lung, kidney, liver, or central nervous system (PMID 8109600). With a median follow up of 6.8 (IQR, 3.5 - 8.9) years, we observed an acute chest syndrome episode complicated by multiorgan failure in 14% (53/391) of SCD patients. A significantly lower proportion of SCD patients with the HP 1-1 isoform developed a multiorgan failure event versus those with the 2-1 or 2-2 isoforms (5.7% vs. 17.2%, respectively; P < 0.001). On logistic regression analysis, acute chest syndrome with multiorgan failure was associated with the HP 1-1 isoform (OR 0.3, 95% CI: 0.1 to 0.6; P = 0.002) and baseline LDH (natural log OR 2.7, 95% CI: 1.2 - 6.3; P = 0.02), after adjusting for age, sex, SCD genotype and hydroxyurea use. In conclusion, we demonstrate that the HP 1-1 isoform is independently associated with higher serum HP concentrations at steady-state as well as during hospitalizations for VOC or acute chest syndrome compared to the HP 2-1 or 2-2 isoforms. Furthermore, the HP 1-1 isoform is protective against developing the devastating multiorgan failure syndrome during acute chest syndrome episodes. Our findings highlight the clinical significance of the HP isoforms and cell-free hemoglobin scavenging in SCD. Future studies assessing HP induction and scavenging function based on HP isoform may help elucidate high-risk patients for aggressive measures, such as rapid initiation of exchange transfusion therapy or HP replacement therapy. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Thrombomodulin and Endothelial Dysfunction in Sickle Cell Anemia

Blood ◽

10.1182/blood-2019-123862 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3558-3558

Author(s):

Maria Armila Ruiz ◽

Binal N. Shah ◽

Jin Han ◽

Rasha Raslan ◽

Victor R Gordeuk ◽

...

Keyword(s):

Endothelial Cell ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Multiorgan Failure ◽

Plasma Concentrations ◽

Organ Damage ◽

Free Hemoglobin ◽

Failure Event

Thrombomodulin (THBD) is a transmembrane protein that regulates endothelial function by 1) binding thrombin and inhibiting its interaction with fibrinogen, 2) augmenting protein C activation, and 3) down-regulating complement activation by inactivating C3a and C5a (PMID 29866818). Reduced THBD function has been implicated in several vasculopathies (PMID 29866818). Oxidative damage increases cleaved non-functional THBD in circulation and increased circulating non-functional THBD predicts the severity of organ damage in thrombotic microangiopathies (PMID 11190905). Vascular endothelial dysfunction is a hallmark feature of sickle cell disease (SCD) that leads to acute and chronic organ damage and may, in part, be mediated by hemolysis (PMID 28248201). Hemolysis leads to release of cell-free hemoglobin which may lead to vasculopathy through consumption of NO, activation of TLR4 pathways, and direct oxidative damage. We investigated whether decreased THBD activity may be implicated in the pathophysiology of SCD vasculopathy in endothelial cells, transgenic sickle mice, and in a prospective cohort of patients with sickle cell anemia. In vitro: We exposed endothelial cells (EA.hy926, ATTC® CRL-2922TM; Manassas, VA) to incremental doses of cell-free hemoglobin. With higher doses of cell-free hemoglobin we observed reduced surface endothelial cell THBD activity at 6 hours of incubation, assessed by cleavage of chromogenic substrate for activated protein C in the presence of thrombin (Figure 1A). In conjunction with the reduced endothelial THBD activity, there were increased concentrations of cleaved THBD in the supernatant by ELISA (R&D Systems, Minneapolis, MN) (Figure 1B). Transgenic sickle mice: At 6 months of age, transgenic sickle mice (Townes model, Jackson Laboratory; Bar Harbor, Maine) had higher plasma concentrations of cleaved non-functional THBD versus hemoglobin AA mice (Figure 2A). Furthermore, staining of the glomerular microvasculature demonstrated decreased endothelial-bound THBD (Figure 2B). Patients with sickle cell anemia: We evaluated whether plasma concentrations of cleaved non-functional THBD are predictive of acute multiorgan failure syndrome (PMID 8109600) in a cohort of 103 SCD patients recruited into a longitudinal kidney cohort study. Clinical and laboratory variables and plasma samples were obtained at the time of enrolment and the patients were monitored prospectively for acute multiorgan failure syndrome. Hemoglobinuria was defined by urine dipstick positive for blood with < 2 red blood cells/high power field. The median age of this cohort was 35 years (interquartile range, 28 - 44 years), 46% were female, 87% had hemoglobin SS genotype, and 47% were on hydroxyurea at the time of enrolment. In cross-sectional analysis, plasma THBD concentrations were greater in patients with hemoglobinuria, a marker of intravascular hemolysis-derived cell-free hemoglobin in circulation exceeding scavenging capability and filtering through the glomerulus, versus without hemoglobinuria (6.1 ± 0.6 µg/mL vs. 3.6 ± 0.4 µg/mL, P = 0.004) (Figure 3A). With a median follow up of 5.5 years (interquartile range, 1.4 - 5.9 years), 18 (17%) SCD patients had a multiorgan failure event. SCD patients with a multiorgan failure event were older (43 vs. 34 years, P = 0.01) but without significant differences in sex, SCD genotype, or hydroxyurea therapy. After adjusting for age, baseline THBD concentrations predicted a greater risk for multi-organ failure syndrome (log-transformed OR 4.0, 95% CI: 1.2 - 13.3; P = 0.01) (Figure 3B). In conclusion, circulating non-functional THBD, a protein that normally functions to reduce vasculopathy when bound to the endothelium, is increased after endothelial cell exposure to incremental doses of hemoglobin in vitro, in hemoglobin SS vs. AA mice, and in SCD patients with versus without hemoglobinuria. Furthermore, circulating THBD is a biomarker that predicted the risk for multi-organ failure syndrome on longitudinal follow up in SCD patients. Future studies investigating the role of THBD in SCD vasculopathy may help improve our understanding for the catastrophic multiorgan failure syndrome and therapies to augment endothelial cell THBD function may guide future intervention practices. Figure 1 Disclosures Gordeuk: Novartis: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria; Pfizer: Research Funding; Inctye: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Imara: Research Funding. Saraf:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding.

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Association of Hospitalization Due to Vaso-Occlusive Crisis with Subsequent Sickle Cell Disease-Related Organ Damage Hospitalization: Retrospective Analysis of 3-Year Observational Study Data

Blood ◽

10.1182/blood-2021-144723 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2037-2037

Author(s):

Matthew M. Heeney ◽

Thirupathi Pattipaka ◽

Jilles M. Fermont

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Gallbladder Disease ◽

Organ Damage ◽

Study Data ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Advisory Committees ◽

History Of

Abstract Background: Hospitalization due to vaso-occlusive crisis (H-VOC) is common in individuals with sickle cell disease (SCD), with an increasing occurrence of SCD-related complications, including organ damage, as the disease progresses. Evidence regarding the relationship between H-VOC and SCD-related organ damage, however, is lacking. Aim: To assess whether H-VOC is associated with hospitalization due to SCD-related organ damage, through retrospective analysis of data collected prospectively during a 3-year, multicenter, observational US study (NCT01220115) that aimed to better understand disease burden and management of SCD in individuals aged ≥2 years. Methods: Of the 498 individuals with SCD who were recruited into the US study, data were analyzed from 202 (100 men and 102 women) who were aged ≥16 years and had available hospital admission data. Organ damage was defined based on hospital discharge diagnosis. 1 Variables tested at baseline, in addition to H-VOC, included demographics, blood measures, and treatment history. Age and sex were included by default in all models based on literature suggesting they are relevant factors influencing organ damage. Hazard ratios (HRs) for the time from H-VOC to the first subsequent hospitalization due to SCD-related organ damage were estimated using multivariable Cox regression. Worsening of pre-existing organ damage was not considered as an event due to potential confounding (ie worsening of organ damage related to the pre-existing condition rather than as a consequence of the VOC). Results: During median 3-year follow-up, 55 (27%) individuals experienced at least one hospitalization due to SCD-related organ damage; 2 19 (9%) had multiple visits. Within the 12 months preceding baseline, 22 (11%) individuals had a history of organ damage, there was a median of two H-VOC in the 90 (45%) individuals with history of H-VOC, and 43 (21%) individuals had received chronic transfusion (≥6). History of H-VOC (HR 2.54, 95% confidence interval [CI] 1.46 to 4.43 in past 12 months), genotype (HR 2.69, 95% CI 1.34 to 5.41 for HbSS), and sex (HR 1.90, 95% CI 1.08 to 3.34 for women) were all significantly associated with subsequent hospitalization for SCD-related organ damage. Discussion and conclusion: This analysis demonstrates that history of H-VOC within the preceding 12 months is significantly associated with a higher rate of subsequent hospitalization due to SCD-related organ damage, independent of age, sex, and genotype, and may therefore help identify individuals at high risk of developing organ damage. Despite 21% of individuals receiving chronic transfusions at baseline, this factor did not remain significantly associated with the outcome when also considering genotype and H-VOC. Age and sex were unexpectedly insignificantly associated with the outcome; this is likely due to the relatively short follow-up time. Extending the historical timeframe of organ damage to 5 years did not change our findings, except that age also became significantly associated with subsequent hospitalization for organ damage. Acute chest syndrome and pneumonia were the most common types of historical (baseline) organ damage, whilst gallbladder disease was the most common organ damage observed during the follow-up period that was not observed at baseline. Our data have limited statistical power and generalizability; additional studies are required to confirm these findings. Nevertheless, our findings support the existing evidence of the impact that VOCs may have on individuals with SCD, and highlights the importance of preventing and reducing H-VOC. 1Acute chest syndrome or pneumonia; avascular bone necrosis of hip(s), shoulder(s) or spine; cardiac failure; central nervous system disease (ie abnormal transcranial Doppler, silent infarct, stroke and transient ischemic attack); gallbladder disease; leg ulcer; liver disease (ie hepatic fibrosis/ cirrhosis, hepatic sequestration/sickle-hepatopathy/intrahepatic sickling, pulmonary fibrosis, pulmonary hypertension); priapism; renal disease (ie acute renal failure, chronic renal failure-supportive, dialysis, microalbuminuria/ proteinuria, transplant); retinopathy; and splenic sequestration. 2The top 3 reasons for hospitalization due to SCD-related organ damage were acute chest syndrome or pneumonia (n=29; 53%), renal disease (n=7; 13%) and gallbladder disease (n=6; 11%). Figure 1 Figure 1. Disclosures Heeney: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; FORMA: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vertex / Crispr Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; bluebird bio: Consultancy; Keros: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Cyclerion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pattipaka: Novartis: Current Employment, Current holder of individual stocks in a privately-held company. Fermont: Novartis Pharma AG, Basel, Switzerland: Current Employment, Current equity holder in publicly-traded company.

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Sickle cell pain: a critical reappraisal

Blood ◽

10.1182/blood-2012-04-383430 ◽

2012 ◽

Vol 120 (18) ◽

pp. 3647-3656 ◽

Cited By ~ 221

Author(s):

Samir K. Ballas ◽

Kalpna Gupta ◽

Patricia Adams-Graves

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Sickle Cell ◽

Multiorgan Failure ◽

Organ Damage ◽

Acute Chest Syndrome ◽

Prodromal Phase ◽

Pain Syndromes ◽

Painful Episode ◽

Chronic Pain Syndromes

AbstractSickle cell pain includes 3 types: acute recurrent painful crises, chronic pain syndromes, and neuropathic pain. The acute painful crisis is the hallmark of the disease and the most common cause of hospitalization and treatment in the emergency department. It evolves through 4 phases: prodromal, initial, established, and resolving. Each acute painful episode is associated with inflammation that worsens with recurrent episodes, often culminating in serious complications and organ damage, such as acute chest syndrome, multiorgan failure, and sudden death. Three pathophysiologic events operate in unison during the prodromal phase of the crisis: vaso-occlusion, inflammation, and nociception. Aborting the acute painful episode at the prodromal phase could potentially prevent or minimize tissue damage. Our hypothesis is that managing these events with hydration, anti-inflammatory drugs, aggressive analgesia, and possibly vasodilators could abort the crisis and prevent or minimize further damage. Chronic pain syndromes are associated with or accompany avascular necrosis and leg ulcers. Neuropathic pain is not well studied in patients with sickle cell disease but has been modeled in the transgenic sickle mouse. Management of sickle cell pain should be based on its own pathophysiologic mechanisms rather than borrowing guidelines from other nonsickle pain syndromes.

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Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽

10.1182/blood-2020-140743 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Rita V Masese ◽

Dominique Bulgin ◽

Liliana Preiss ◽

Mitchell Knisely ◽

Eleanor Stevenson ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Transfusion Requirement ◽

The United States ◽

Acute Chest Syndrome ◽

Maternal Outcomes ◽

Maternal Complications ◽

Advisory Committees ◽

Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

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Comparison of Steady-State Imatinib (IM) Trough Levels, Clinical Response, and Safety Between Caucasian and Asian Patients with Chronic Lyeloid Leukemia in Chronic Phase (CML-CP) Treated with 400mg and 800mg Daily Doses of IM in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) Study.

Blood ◽

10.1182/blood.v114.22.1127.1127 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1127-1127

Author(s):

Dong-Wook Kim ◽

Camille Granvil ◽

Eren Demirhan ◽

John Reynolds ◽

Yu Jin ◽

...

Keyword(s):

Adverse Event ◽

Steady State ◽

Clinical Response ◽

Board Of Directors ◽

Research Funding ◽

Average Dose ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3 ◽

Trough Levels

Abstract Abstract 1127 Poster Board I-149 Background In the TOPS study, IM trough levels (Cmin) were collected from different race groups, mainly Caucasian and Asian, but also Black and others. Inter-ethnic differences in the PK of a drug are known to be important factors accounting for inter-individual variation in drug responsiveness. This analysis reports the comparison between Caucasian and Asian CML patients (pts) treated at doses of 400 mg QD and 400 mg bid (800 mg daily) of IM Cmin on Day 29 of initial treatment, clinical response, safety and tolerability. Methods Steady state IM Cmin on Day 29 and clinical response and safety data obtained during the first 12 months (mos) of treatment were obtained from pts randomized 2:1 to 800 mg or 400 mg daily IM. The steady-state Cmin was defined as predose concentration collected approximately within ±3 hours of the scheduled dosing time on Day 29. The associations of race with the rates of major molecular response (MMR) and complete cytogenetic response (CCyR) were evaluated. Correlation of IM exposure with clinical response (MMR and CCyR) was assessed by grouping pts into quartiles based on their measured IM Cmin levels at Day 29. The safety endpoint for each pt was the presence or absence of an adverse event (AE) of grade 3 or higher in the first 12 mos from the first dose. Results IM Cmin levels were available from 229 pts in TOPS including 54 Caucasians, 18 Asians, and 14 Black and others at 400 mg (total 86) and 103 Caucasians, 29 Asians, and 11 Black and others at 800 mg (total 143). For the first 12 mos, the means of the average dose intensities for Asian (mean [range], 362 [267-400] in 400 mg and 666 [226-800] in 800 mg) were not significantly different from Caucasian (386 [204-597] in 400 mg and 666 [289-800] in 800 mg) (P=0.070 and P=0.995 for the 400 mg and 800 mg arms, respectively). Mean (± SD) of IM Cmin levels (ng/mL) with respect to race are shown in Table 1. IM Cmin was slightly over-proportional to dose and showed large interpatient variability (CV=42-60%) for both dose groups regardless of the race group. In the lower quartile Cmin group (Cmin<1290 ng/mL), the differences in CCyR and MMR rates between Asian and Caucasian pts were significant (P=0.031 and P=0.022 respectively), which was probably due to a higher rate of dose interruptions in the 1st 12 mos in Asian pts. A definitive conclusion cannot be drawn due to the small number of Asian pts. Occurrences of at least one grade 3 or 4 adverse event were found to be significantly higher in Asian pts (69% and 75% in the 1st 6 and 12 mos respectively) compared to Caucasian pts (53% and 57% in the 1st 6 and 12 mos respectively) (P=0.028 and P=0.008 respectively). Conclusion The results of this analysis from TOPS show that IM Cmin levels were similar between Caucasian and Asian CML pts in each treatment arm. There were no major differences in efficacy, as measured by MMR and CCyR rates by 12 mos, between Asian and Caucasian pts. There were no unexpected differences in patterns of AEs between Caucasian and Asian pts; however, occurrences of one or more grade 3 AEs were higher in Asian. Further analysis on a larger group of CML pts will be needed to evaluate the impact of AE rate differences between Caucasian and Asian pts. Disclosures Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Granvil:Novartis: Employment. Demirhan:Novartis: Employment. Reynolds:Novartis: Employment. Jin:Novartis: Employment. Wang:Novartis: Employment, Equity Ownership. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria.

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The Majority of Patients with Relapsing Light Chain (AL) Amyloidosis Are Not Eligible for Enrollment Onto Clinical Trials: Using Screen Failures to Define Major Unmet Medical Needs

Blood ◽

10.1182/blood.v126.23.1786.1786 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1786-1786 ◽

Cited By ~ 1

Author(s):

Heather Landau ◽

Raymond L. Comenzo ◽

Tasneem Balasinorwala ◽

Melissa Warner ◽

Ola Landgren ◽

...

Keyword(s):

Clinical Trials ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Organ Damage ◽

M Protein ◽

Al Amyloidosis ◽

Advisory Committees ◽

Medical Needs ◽

Measurable Disease

Abstract Background: Hematologic response criteria in AL amyloidosis are based on reduction of FLCs and correlate with organ improvement and survival in the front-line setting (Palladini 2012). Hematologic progression is defined from complete response (CR) as any detectable monoclonal (m) protein or abnormal FLC ratio (light chain must double); and from partial response (PR) as a 50% increase in serum or urine m-protein to > 0.5g/dl or 200mg/d respectively; or a 50% increase in FLC to > 10mg/dL based on consensus criteria (Gertz 2005); while cardiac and renal progression criteria have recently been validated (Palladini 2012 & 2014). Trials enrolling relapsed pts define measurable disease by a difference in FLC (dFLC) >5mg/dl such that accurate responses (VGPR, PR) can be assessed. However, many pts with hematologic and/or organ progression fail to meet dFLC > 5mg/dL set by inclusion criteria (if progression from CR) or the high bar of FLC > 10mg/dL set by the progression criteria and are ineligible for clinical trials. Composite criteria for progression of disease involving both hematologic measures and biomarkers of organ damage do not exist. The goal of the current study was to characterize pts with AL and evidence of progressive disease who were ineligible for clinical trials in order to determine the magnitude of this problem and define potential AL study populations whose medical needs are not being met. Methods: Previously treated AL pts screened for clinical trials from 5/2013 to 5/2015 at Memorial Sloan Kettering Cancer Center and Tufts Medical Center were reviewed retrospectively. Trials included 1) phase I/II trial of carfilzomib (NCT01789242), 2) phase I trial of ixazomib (NCT01318902) and 3) phase III trial of ixazomib/dexamethasone versus physician's choice (NCT01659658). Inclusion for all 3 required relapsed AL with dFLC >5mg/dl and evidence of organ damage. Pts with progressive hematologic and/or organ disease (by consensus or validated criteria) who were screened for these trials were included in this analysis. Results: Among 36 pts screened, 33% (N=12) enrolled. Yet, 67% (N=24) with hematologic (N=14), cardiac (N =6) and/or renal (N=11) progression were ineligible. Median age was 61 years (range, 41-78); prior lines of therapy were 1 in 38%, 2 in 38% and >2 in 25%. Median BNP, TROP, serum ALB, eGFR and 24hr urine total protein were: 283pg/mL (36-2197), 0ng/mL (0-0.09), 3.4g/dL (1.3-4.8), 66ml/min (7-128) and 1800 mg/24hrs (trace-12,875), respectively. Median involved FLC was 6.48mg/dl (0.93-52.6) and dFLC 4.69mg/dl (0.01-52). 58% (14/24) were ineligible due to dFLC <5mg/dl, which was the most common reason for screen failure despite meeting hematologic and/or organ criteria for progression. Others were excluded for multiple myeloma (N=2), cardiac stage III (N=4), prior malignancy (N=1), number of prior therapies (N=1) and low creatinine clearance (N=2). 92% (22/24) have received therapy: 19 off study, 2 on alternate trials and 1 eventually qualified with dFLC >5mg/dl; 2 are being monitored for FLC progression with unclear clinical implications. One-third of patients ineligible for these trials have died. Conclusions: The finding that only 1/3 of pts with AL amyloidosis and hematologic or organ progression requiring therapy are eligible for clinical trials demonstrates the limitations of the current definitions of progression and "measurable disease" criteria for enrolling relapsed pts on trials. The necessary decision to treat pts with organ progression in advance of their meeting a criterion for FLC progression (to >10mg/dl) indicates that this arbitrarily defined value needs to be revised. Moreover, time to next therapy rather than progression free survival (as currently defined) is a more relevant clinical trial end point. More sensitive, validated hematologic progression and composite criteria defining progression of hematologic and organ disease are critically needed to identify patients whose level of hematologic disease progression and risk of organ damage is at variance with current criteria as defined by FLCs. This will enable novel therapies that have the potential to reduce the risks of end-stage organ failure and death to be tested in this population. Disclosures Landau: Spectrum Pharmaceuticals: Honoraria; Prothena: Consultancy, Honoraria; Onyx: Honoraria, Research Funding; Janssen: Consultancy; Janssen: Consultancy; Takeda: Research Funding. Comenzo:Prothena: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Takeda Millennium: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees. Landgren:BMJ Publishing: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Medscape: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy. Giralt:CELGENE: Consultancy, Honoraria, Research Funding; TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding.

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A Longitudinal Study to Identify and Assess Adhesion Indices during Vaso-Occlusive Crises in Adults and Adolescents with Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-120311 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1097-1097

Author(s):

Jennell White ◽

Xiufeng Gao ◽

Ke Liu ◽

Michael U. Callaghan ◽

Patrick C. Hines

Keyword(s):

Steady State ◽

Longitudinal Study ◽

Board Of Directors ◽

Research Funding ◽

Cell Disease ◽

Advisory Committees ◽

Blood Samples ◽

Equity Ownership ◽

Adhesion Index ◽

At Home

Abstract Sickle cell disease (SCD) is characterized by frequent and unpredictable vaso-occlusive complications (VOCs); however, there are no objective measures for VOC as a clinical endpoint. Vaso-occlusion results from processes that reduce blood flow in the microvasculature, including red cell stickiness and erythrocyte sickling. These processes lead to pain, chronic organ damage, and decreased life expectancy. The decision to seek medical contact varies amongst patients. When VOCs are managed at home valuable information remains unknown. We designed a longitudinal, observational study to capture adhesion data at home and in a hospital setting. The objective of this study was to determine whether a standardized, flow-based adhesion bioassay is capable of identifying VOCs occurring in SCD patients with varying degrees of medical contact. SCD patients (n=33) were evaluated over a 6-month period. Blood samples were collected every 3 weeks; when patients report a VOC corresponding blood samples are collected and steady state samples are resumed. During 6 months of evaluation, longitudinal measures of pain and clinical laboratory and biomarker samples from SCD patients (+/- hydroxyurea therapy) in steady state to VOC were studied. Blood samples were collected in sodium citrate from SCD subjects at steady state and during VOCs. Blood samples were perfused through VCAM-1-coated microchannels at standard physiologic flow conditions (1dyne/cm2, 1.67Hz). An adhesion index was established by quantifying adherent cells within a standard viewing area (cells/mm2), and could be obtained within 6-9 min. Adhesion indices varied from sample-to-sample at baseline (n=289; mean = 355 ± 235; median = 297 cells/mm2) and during VOC (n=59, mean=416±233, median=390). Repeated measures of adhesion over 6 months reveals significant intra-patient associations with C-reactive protein (CRP, n=335, r=0.16; p=0.006), lactose dehydrogenase (LDH, n=336, r=0.12; p=0.032), white blood cells (WBC, n=341, r=0.13; p=0.019), and reticulocyte percent (n=336, r=0.37, p<0.0001). The results also show significant inter-patient (n=35) correlations with CRP (r=0.34, p=0.047), fetal hemoglobin (HbF, r=-0.61, p=0.0001), reticulocyte percent (r=0.63, p<0.0001), reticulocyte (r=0.77, p<0.0001), and uric acid (r=0.37, p=0.028). At-home VOC adhesion indices (n=33; mean=482±255) were significantly higher than both ER-based VOC (n=8; mean=322± 153; p=0.031) and hospital-based VOC (n=18, mean=336±182; p=0.018) adhesion indices. The difference between at home VOC adhesion indices and baseline adhesion indices approached significance (482 ± 255 vs 355 ± 235, p=0.088). This study represents the largest longitudinal study of adhesion indices using a standardized clinical assay. These data confirm the normal range and longitudinal variability of SCD adhesion indices at baseline and during VOC. Adhesion increased during patient-reported VOCs in a subpopulation of individuals with SCD, suggesting there may be a subphenotype who are more predisposed to adhesion-mediated VOCs. At-home VOCs are likely higher because ER-VOC indices are influenced by fluid boluses, blood transfusions, or anti-inflammatory therapy. Further studies are underway to determine if a clinical adhesion index can effectively monitor response to SCD-modifying therapies and prospectively predict disease progression. Disclosures White: functional fluidics: Equity Ownership. Gao:Functional Fluidics: Equity Ownership. Liu:Functional Fluidics: Equity Ownership. Callaghan:Bioverativ: Honoraria; Alnylam Pharmaceuticals: Equity Ownership; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria; Sancilio Pharmaceuticals Company: Employment; Novo Nordisk: Employment, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hema Pharmaceuticals: Honoraria; Grifols: Honoraria; Pfizer: Employment, Honoraria, Research Funding; Roche/Genentech: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Employment; Global Blood Therepeutics: Employment. Hines:functional fluidics: Equity Ownership.

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A Critical Role for Intratumoral and Circulating LAG3 in Classical Hodgkin Lymphoma: Analysis from the Rathl Prospective Phase III International Clinical Trial

Blood ◽

10.1182/blood-2018-99-112008 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1621-1621

Author(s):

Emad Uddin Abro ◽

Soi C Law ◽

Colm Keane ◽

Simone Birch ◽

Muhammed Bilal Sabdia ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Discovery Cohort ◽

Serum Samples ◽

Advisory Committees ◽

A Cell ◽

Education Support

Abstract In classical Hodgkin lymphoma (CHL) the tumor microenvironment (TME) is enriched in T cells that modulate antitumor immunity. PD1 blockade partially restores anti-tumoral T cell function, to induce impressive responses in a proportion of patients with relapsed/refractory CHL (Chen et al JCO 2017). Further characterisation of T cell immune evasion mechanisms in CHL will permit the rational development of enhanced immunotherapeutic strategies. Lymphocyte-activation gene 3 (LAG3) is a cell surface molecule known to be expressed on a subset of immune effector T cells and intratumoral regulatory T cells (Tregs) in solid-organ tumors, with combination PD1/LAG3 mAb blockade showing early promise (Ascierto et al 2017 JCO abst 9520). In contrast, data in haematological malignancies is limited, although it is known that LAG3+ T cells suppress anti-tumoral immunity in CHL and B-CLL (Gandhi et al Blood 2006; Shapiro et al Haematologica 2017). Interestingly, in B-CLL LAG3 is found on both T cells and malignant B cells. Whether Hodgkin Reed-Sternberg (HRS) cells express LAG3 is unknown. To characterise in detail intratumoral and circulating LAG3 in CHL we used a conventional discovery / validation approach. The local institutional discovery cohort was drawn from Princess Alexandra Hospital in Brisbane (Australia), and validated in samples from the prospective randomised phase III international "RATHL" trial (Johnson et al NEJM 2016). Firstly, LAG3 gene expression (GEP) was digitally quantified by NanoString in FFPE tissues in the discovery cohort and compared to normal control nodes and DLBCL tissues. Normalised LAG3 mRNA counts were 5-10-fold higher in CHL than in controls (P < 0.001) and 3-5-fold higher than in DLBCL (P < 0.001), whereas PD1 and TIM3 mRNA counts did not differ. In CHL samples LAG3 mRNA counts were markedly increased compared to PD-1 axis molecules and TIM3 (P < 0.001) (Figure 1a). Higher levels of LAG3 mRNA counts were correlated with infiltration by T cells (CD4 r = 0.55; P < 0.00001; CD8 r = 0.51, P < 0.0001), and macrophages (CD68 r = 0.45; P = 0.002). Findings were replicated in the RATHL cohort. Next, intratumoral LAG3 cellular distribution was established. Flow cytometry was used to quantify LAG3 in T cell subsets and CD30+CD3- HRS cells in 6 de-aggregated freshly frozen CHL nodes (TILs). LAG3 was evenly distributed between CD8+ T cells, CD127LOCD25HI natural-Tregs (nTregs) and CD127LOCD25LO induced-Tregs (iTregs), but with minimal expression on CD4 non-Tregs, with the latter constituting the majority of intratumoral T cells. LAG3+ T cells typically co-expressed PD1 and/or TIM3. LAG3 was expressed on CD30+CD3+ cells but not on CD30+CD3- cells, consistent with LAG3 expression on activated T cells. Multispectral immunofluorescence (mIF) image analysis confirmed these findings in histological tumor samples (Figure 1b). Also, there was negligible expression of LAG3 on HRS-lines. Finally, the potential role of soluble LAG3 (sLAG3) as a rapid-turnaround circulating biomarker applicable to the routine diagnostic laboratory, was assessed in serum samples using the MSD R-PLEX assay. In the discovery cohort sLAG3 was 3-4-fold increased at pre-therapy compared to controls and 3-6M post-therapy serum (P = 0.001). Results from pre-therapy RATHL serum samples were similar (P < 0.05). Notably in RATHL samples at interim restaging after 2 ABVD cycles sLAG3 had reduced by ~5-fold compared to pre-therapy (P < 0.0001) in patients with PET/CT responsive disease (Figures 1 c + d). Twelve months post therapy sLAG remained significantly lower than pre-therapy (P < 0.05) and was equivalent to control samples. Pre-therapy serum sLAG3 demonstrated a modest correlation with tissue LAG3 mRNA counts (r = 0.45; P = 0.02). In conclusion in CHL, LAG3 mRNA expression was markedly increased relative to control and DLBCL tissues. Within CHL tissues LAG3 mRNA was markedly increased compared to other immune checkpoint molecules. Interrogation of the TME using flow cytometry of TILs and mIF demonstrated LAG3 is evenly distributed between CD8+, nTregs and iTRreg. In tumor samples we did not find evidence of LAG3 expression on HRS cells. To our knowledge this is the first study to demonstrate sLAG3 as a cell free circulating disease response biomarker in CHL. Taken together these findings provide a convincing rationale for further exploration of single and/or combined checkpoint blockade incorporating LAG3 inhibition to treat CHL. Disclosures Abro: Bristol-Myers Squibb: Speakers Bureau; Janssen: Other: education support congress attendance; Celgene: Other: education support congress attendance; Novartis: Consultancy; Amgen: Other: education support congress attendance. Keane:BMS: Research Funding; Roche: Other: Education Support, Speakers Bureau; Celgene: Consultancy, Research Funding; Takeda: Other: Educational Meeting; Merck: Consultancy. Birch:Medadvance: Equity Ownership. Tobin:Amgen: Other: Educational Travel; Celgene: Research Funding. Johnson:Kite: Consultancy; Celgene: Honoraria; Eisai: Research Funding; Incyte: Consultancy; Takeda: Honoraria, Travel, accommodations, expenses; Janssen: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Honoraria; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Bristol-Myers Squibb: Honoraria; Boeringher Ingelheim: Consultancy; Epizyme: Consultancy, Honoraria, Research Funding. Trotman:F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding. Bird:Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gill:Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Gandhi:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Midostaurin (PKC412) Demonstrates a High Rate of Durable Responses in Patients with Advanced Systemic Mastocytosis: Results from the Fully Accrued Global Phase 2 CPKC412D2201 Trial

Blood ◽

10.1182/blood.v124.21.636.636 ◽

2014 ◽

Vol 124 (21) ◽

pp. 636-636 ◽

Cited By ~ 5

Author(s):

Jason Gotlib ◽

Hanneke C. Kluin-Nelemans ◽

Tracy I. George ◽

Cem Akin ◽

Karl Sotlar ◽

...

Keyword(s):

Mast Cell ◽

Research Funding ◽

Systemic Mastocytosis ◽

Organ Damage ◽

High Rate ◽

Advisory Committees ◽

Laboratory Services ◽

Grade 3 ◽

Stage 1 ◽

Kit D816v

Abstract Background: Patients (pts) with advanced systemic mastocytosis (SM), including aggressive SM (ASM) and mast cell leukemia (MCL) ± associated clonal hematologic non–mast cell lineage disease (AHNMD), have a poor prognosis with few effective treatment options. More than 80% of pts express the activating KIT D816V mutation. The oral multikinase inhibitor midostaurin inhibits wild-type and D816-mutated KIT. In this global phase 2 trial (NCT00782067), the largest prospective trial in advanced SM, a planned interim analysis of stage 1 pts demonstrated a high overall response rate (ORR) with reductions in marrow mast cell (MC) burden and a favorable safety profile (Gotlib et al, Blood 2012). Updated stage 1 results showed improvements in symptoms and quality of life (QOL) (Gotlib et al, Blood 2013). Here, we report primary results for the fully accrued trial. Methods: This single-arm trial consisted of an adapted Fleming 2-stage design. Midostaurin 100 mg twice daily was administered in continuous 28-day cycles until progression or unacceptable toxicity. Eligibility and responses (modified from Valent et al,Leuk Res 2003) were adjudicated by study steering committee (SSC). Histopathology was centrally assessed. Eligible pts had ≥ 1 measurable C-finding (CF) defined as SM-related organ damage. The primary endpoint was ORR (major response [MR] + partial response [PR]) occurring in the first 6 cycles and maintained for ≥ 8 weeks (wk). Results: Of 116 enrolled pts, 89 (77%) were eligible for efficacy evaluation; pts were considered ineligible by the SSC due to absence of measurable CF (n = 14) or organ damage considered unrelated to SM (n = 13). Median age was 64 years (range 25-82). Overall, 73 pts (82%) had ASM, including 57 (78%) with an AHNMD (ASM-AHNMD); 16 (18%) had MCL, including 6 (38%) with an AHNMD (MCL-AHNMD). AHNMDs included chronic myelomonocytic leukemia (n = 25), myelodysplastic/myeloproliferative neoplasm unclassifiable (n = 22), hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL; n = 5), and 11 other subtypes. A total of 37 pts (42%) had received ≥ 1 prior therapy (median 1; range 1-4). Seventy-seven pts (87%) were positive and 10 pts (11%) were negative for KIT D816V/Y/L mutation; 2 pts were not evaluable. The ORR was 60% (53/89); most responses were MRs (40/53, 75%), subtyped as incomplete remission (IR) in 36%, pure clinical response in 28%, and unspecified in 11%. PRs included good PR (GPR) in 21% and minor PR in 4% of pts. Overall, 12%, 11%, and 17% of pts had stable disease, progressive disease, or were not evaluable for response, respectively. After a median follow-up of 26 months (mo; range 12-54), the median duration of response (DOR) and median overall survival (OS) were 24.1 and 28.7 mo, respectively (Figure). Median OS in responders was 44.4 mo. Of 16 MCL pts, 8 responded, including 7 MRs (44%); median DOR was not reached (NR), with 3 IRs ongoing (49+, 33+, and 19+ mo). Median OS was 9.4 mo among all pts with MCL and NR among responders. Median change in MC burden in 72 evaluable pts was -59% (range -96% to 160%); 41 pts (57%) had ≥ 50% reduction. Median best change in serum tryptase level in 89 evaluable pts was -58% (range -99% to 185%); 32 pts (36%) had ≥ 50% reduction lasting ≥ 8 wk. Four of 5 responding ASM/MCL-HES/CEL pts (1 IR, 3 GPR) also had complete resolution of eosinophilia (mean % and absolute eosinophils at baseline: 57% and 12.4 × 109/L). Improvements in symptoms and QOL were consistent with those reported previously (Gotlib et al, Blood 2013). All 116 pts received ≥ 1 midostaurin dose and were evaluable for safety. Grade 3/4 drug-related hematologic adverse events (AEs) were neutropenia (5%), leukopenia (4%), febrile neutropenia (3%), anemia (3%), and thrombocytopenia (3%). Low-grade nausea was common but usually manageable with antiemetics. The most frequent grade 3/4 drug-related non-hematologic AEs included nausea (6%), vomiting (6%), fatigue (4%), and increased lipase/amylase (4%/3%). As of July 9, 2013, 65 pts had discontinued therapy, most commonly due to progression (n = 31) and AEs (n = 18; 11 were considered drug related [3 hematologic and 8 non-hematologic AEs]). Seven patients developed acute myeloid leukemia related to a prior AHNMD. Conclusions: Midostaurin exhibits a high rate of durable responses in pts with advanced SM, particularly in MCL, which has a dismal prognosis. The reductions in MC burden suggest that midostaurin may impact the natural history of the disease. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Gotlib: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Support Other. George:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Akin:Novartis: Consultancy. Sotlar:Novartis Pharma: Laboratory Services, Laboratory Services Other; Nanostring Technologies: Consultancy. Hermine:Novartis: Research Funding. Awan:Boehringer Ingelheim: Consultancy; Lymphoma Research Foundation: Research Funding. Mauro:Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Oncology: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Speakers Bureau. Sternberg:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Villeneuve:Novartis Pharma AG: Employment. Emery-Salbert:Novartis: Employment. Stanek:Novartis Pharmaceuticals Corporation: Employment. Hartmann:Novartis: Consultancy. Horny:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding. Reiter:Novartis: Consultancy, Honoraria.

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An Analysis Of The Pediatric Sub-Group From The Phase 2 Study Of GMI 1070 – A Novel Agent For The Vaso-Occlusive Crisis Of Sickle Cell Anemia

Blood ◽

10.1182/blood.v122.21.2206.2206 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2206-2206

Author(s):

Timothy L. McCavit ◽

Lakshmanan Krishnamurti ◽

Lewis L. Hsu ◽

Charles T. Quinn ◽

Isaac Odame ◽

...

Keyword(s):

Median Time ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Study Drug ◽

Acute Chest Syndrome ◽

Phase 2 ◽

Opioid Use ◽

Advisory Committees ◽

Secondary Outcomes

Abstract Introduction Vaso-occlusive crisis (VOC) is the hallmark of sickle cell anemia (SCA), yet VOC treatment has not improved in decades. Recently the role of adhesive interactions between leukocytes, erythrocytes, and the vascular endothelium has been recognized in VOC. GMI 1070, a pan-selectin inhibitor, was designed to decrease the contribution of leukocyte adhesion to VOC. Herein, we report a sub-analysis of the pediatric patients enrolled in a study of GMI 1070 with the aims of determining the efficacy and toxicities in this subgroup and comparing pediatric to adult patients. Methods This multi-center, randomized, double-blind, placebo-controlled phase 2 trial enrolled afebrile patients ≥ 12 yrs with HbSS or HbSβ0 thalassemia presenting with VOC. Subjects had no organ dysfunction or other acute SCA complications. GMI 1070 was administered IV as a loading dose, then in up to 14 q12 h maintenance doses. Following a pre-specified interim PK analysis including 1 pediatric and 10 adult subjects, the loading and maintenance doses were doubled. Other management was at the discretion of the treating physician. Pain intensity was measured with a 10 cm visual analog scale. The primary outcome was time to resolution of VOC, defined as either a sustained 1.5 cm decrease in the pain score and cessation of IV analgesics; readiness for discharge; or hospital discharge. Secondary outcomes included time to discharge, time to transition from IV to oral analgesics, opioid usage, and safety profile. Median time-to-event was compared between arms using the Kaplan-Meier (KM) method. Analysis of covariance was used to compare the mean hourly opioid use, by hospital day. Results Seven sites enrolled 20 pediatric subjects: GMI 1070 - 13 vs placebo - 7. The median age was 14 years, and 40% were female. Time to 1st dose of study drug was a mean of 15 h from initial medical evaluation. Median length of stay was 105 h. The GMI 1070 arm had a 60.7 h reduction in the median time to resolution of VOC compared to placebo (Fig. 1a). Similarly, the median difference in time to transition to oral opioids and time to discharge were clinically significant between GMI 1070 and placebo at 87.8 h and 96 h, respectively (Fig. 1b & 1c). Mean hourly opioid use was lower with GMI 1070 than placebo in the first 24 h, but the trajectory thereafter did not differ (Fig. 1d). The effect of GMI 1070 on the primary and secondary outcomes was similar for pediatric and adult subjects (Table 1). Differences between pediatric and adult subjects included which opioid was used (pediatrics – 80% morphine vs adults – 80% hydromorphone). Also more pediatric subjects received IV antibiotics (Table 1), particularly in the first 24 hrs of study drug (pediatrics – 35% vs adults – 14%). The proportion of pediatric subjects experiencing a serious adverse event (SAE) was similar between arms (GMI 1070 – 31% vs placebo – 43%). Most SAE's were VOC recurrence; 1 SAE was an episode of acute chest syndrome (ACS) in the GMI 1070 arm (0 in the placebo arm). Of 4 total ACS events (1 SAE, 3 AE), 3 occurred within 24 h of 1st study drug, 1 required red blood cell transfusion and 0 required intensive care. No severe or unusual infections occurred in either arm. Conclusions GMI 1070 is a promising agent for reducing duration of VOC in SCA. Compared to adults, pediatric subjects demonstrated similar efficacy and safety. The ACS cases in the GMI 1070 arm are noteworthy but are not definitively associated with study drug. The strong efficacy signal in adolescents, along with minimal safety concerns, warrants inclusion of younger children in a subsequent phase 3 clinical trial of GMI 1070. Disclosures: McCavit: Pfizer, Inc.: Consultancy; GlycoMimetics, Inc.: Research Funding. Krishnamurti:GlycoMimetics, Inc.: Research Funding. Hsu:GlycoMimetics, Inc.: Research Funding. Quinn:Glycomimetics: Research Funding; Eli Lilly: Research Funding; MAST Therapeutics: Research Funding; American Society of Hematology: Advisory Committees, Advisory Committees Other, Honoraria. Odame:Glycomimetics: Research Funding. Alvarez:Glycomimetics: Research Funding. Driscoll:Glycomimetics: Research Funding. Smith-Whitley:GlycoMimetics, Inc: Research Funding. Rhee:Rho, Inc.: Employment; GlycoMimetics, Inc.: Research Funding. Wun:Emmaus, Inc.: Clinical Adjudication Committee Other; Pfizer, Inc.: Consultancy; GlycoMimetics: Research Funding. Telen:GlycoMimetics, Inc.: Research Funding; Dilaforette, NA: Research Funding; Pfizer, Inc.: Consultancy. Thackray:GlycoMimetics, Inc.: Employment, Equity Ownership.

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