ALBERT

Description: Background and purpose: There are no currently approved treatments for the vaso-occlusive crises (VOC) associated with sickle cell disease (SCD). In addition to causing pain, vaso-occlusion and the resulting hypoxia cause a reduction in overall life expectancy and increase chronic morbidity. Sevuparin is a novel, non-anticoagulant, low-molecular weight heparin analogue, with a preclinical multi-modal activity profile against VOC relevant targets (i.e. P- and L-selectin, thrombospondin, Von Willebrand factor, fibronectin). Due to its low risk for bleeding side effects, sevuparin can be dosed at levels that were previously unattainable with heparinoids. The present study evaluated whether sevuparin could shorten the time with VOC in hospitalized SCD patients compared to placebo. Patients and methods: This phase II, global, multicenter, randomized, double-blind, placebo-controlled and parallel group clinical trial enrolled patients aged 12 to 50 with a diagnosis of SCD (HbSS, HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia). The study recruited patients across 22 sites in 8 countries (Netherlands, Belgium, Turkey, Oman, Bahrain, Lebanon, Saudi Arabia, and Jamaica). Patients with VOC received sevuparin or placebo (1:1) along with standard of care (SoC) therapy with a requirement for parenteral opioid use. The primary endpoint was time to VOC resolution, measured as the time from IMP start until resolution by fulfilment of the two following criteria: a) freedom from parenteral opioid use (8 ± 2 hours), b) readiness for discharge as judged by the patient or physician (whichever occurred first). In addition to assessing safety, main secondary efficacy measures were related to pain and opioid use. The sample size of 120 VOC resolution events was determined based on an assumed between-arm hazard ratio of 0.60. Results: Overall, 147 subjects were randomized (144 dosed) to sevuparin, n=71 (69); or placebo n=76 (75). The median age of subjects entering the study was 22 years with 72% adults and 62,5 % males. Treatment groups were generally balanced with respect to demographic and baseline characteristics. Sevuparin, infused continuously at 18 mg/kg/day, did not confer any benefit over placebo in the primary endpoint of time to VOC resolution (ITT Cox proportional HR 0.89 (95% CI 0.61-1.30; p = 0.554; Figure 1a), which was also reflected by the secondary endpoint analyses (exemplified in Figure 1b). Most AEs were mild to moderate and transient. The number of SAEs was slightly higher in the placebo group (21/17 [22.4%]; one fatal case with hyperhemolytic crisis) than in the sevuparin group (16/15 [22.1%]). The most commonly reported treatment emergent AEs (TEAEs) are displayed in Table 1. No clinically meaningful differences, imbalances or trends were apparent in TEAEs, laboratory parameters, vital signs, physical examination and ECG data across treatment groups. Conclusions: In this study, one of the largest VOC studies run to date, sevuparin failed to show an improvement of the VOC resolution time and associated measures (pain, opioid use, etc) in patients hospitalized with acute VOC. These results were surprising given both the promise from preclinical models and the clinical efficacy seen with selectin inhibition. It is possible that once full-blown, an acute VOC cannot be limited by sevuparin's mode of action (MoA). The understanding of sevuparin's MoA combined with this negative result may contribute to the notions of VOC causative factors and help inform future therapeutics targeting the VOC. The study is also important given its size and the high patient representation from the eastern Mediterranean and Middle Eastern regions, where SCD is of high prevalence. The comparison of this data with the available data from other VOC studies will be important in helping understand both regional and genetic differences in treatment practices and response to therapeutics. In conclusion, the present study showed that sevuparin treatment was not effective in acute VOC. However, sevuparin's promising safety profile and broad MoA including p-selectin inhibition, may warrant further exploration in the prodromal setting, especially given that sevuparin may be dosed by the patient at home in a convenient, subcutaneous format. Acknowledgements: Modus is grateful for the contributions from Ergomed, the Arabian Gulf University, the study sites, as well as to the patients for participating in this study. Disclosures Al-Khabori: Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; NovoNardisk: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria; AstraZeneca: Honoraria. Abboud:CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Other: Travel support; Modus: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Inati:Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Research Funding; AstraZeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kristensen:Modus Therapeutics: Employment. Donnelly:Modus Therapeutics: Employment. Ohd:Modus Therapeutics: Employment.

Description: Abstract 1066 Fetal hemoglobin (Hb F) induction (anti-switching therapy) is an effective therapeutic strategy in sickle cell disease (SCD), both for reducing acute complications such as painful episodes and acute chest syndrome, and decreasing hospitalizations and transfusion requirements. Long term use of the only approved anti-switching agent, hydroxyurea (HU) has also been shown to improve survival. Despite this, HU is still not widely prescribed, ∼30% of patients are non-responders, and there are concerns regarding long term use of this cytotoxic agent. There is, therefore, a clear need for alternative anti-switching agents with different mechanism(s) of action, that are not cytotoxic, and that could be used either alone, or in combination with HU to enhance Hb F response. HQK-1001, an orally bioavailable short-chain fatty acid, was shown to promote Hb F synthesis and prolong erythroid survival and proliferation in transgenic mice and non-human primate models. In a Phase 1/2, dose-escalation, placebo-controlled study in 24 patients with SCD, HQK-1001 given at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated, showed dose-proportional pharmacokinetics (PK), and resulted in dose-dependent increase in Hb F (A Kutlar et al, Blood 2010; 116: Abstract 943). This randomized open-label Phase 2 study is being conducted to evaluate the safety, PK, and effect on Hb F of HQK-1001 administered at a higher dose and for a longer duration than previously studied. Patients with SCD age 12 years and greater were randomized to receive HQK-1001 at 30 or 40 mg/kg daily for 26 weeks. Enrollment at the 50 mg/kg dose level was opened after the Safety Monitoring Committee conducted a planned interim safety data review of the first 12 patients treated for 4 weeks. HQK-1001 is administered as 900 mg tablets, and daily oral iron supplementation is given to patients with plasma ferritin levels less than 700 ng/mL. A minimum of 14 patients stratified 1-to-1 by HU use at baseline will be enrolled at each dose level. Between 25 April 2011 and 5 August 2011, 39 patients have been enrolled and received HQK-1001 at 30 mg/kg (n = 14), 40 mg/kg (n = 14), and 50 mg/kg (n = 11). Patients were enrolled in North America (n = 18), Lebanon (n = 15) and Egypt (n = 6). Median age was 22 years (range, 12–47) and 7 (18%) were less than 18 years old. There were 20 (51%) males and 19 (49%) females. Patients had either Hb-SS (n = 34) or Hb-Sβ0 (n = 5), and 25 (64%) were on HU at baseline and continued HU while on study. Four patients have discontinued HQK-1001 per protocol following a transfusion to treat a SCD complication. One patient discontinued HQK-1001 due to pancreatitis. This patient was found to have a stone in the common bile duct and subsequently died postoperatively from multiorgan failure. The most common adverse events considered by the investigator as possibly drug-related were nausea in 10 patients (26%), abdominal/epigastric pain, vomiting, and headache in 5 (13%) each, and somnolence and dizziness in 3 (8%) each. Drug-related adverse events were graded as mild or moderate except for 1 case each of pancreatitis and gastritis graded as severe. No myelosuppression was observed. Assessment of HQK-1001 effect on Hb F and hemoglobin (Hb) is limited due to short follow-up. In 19 patients in which baseline and Week 4 data are available, the mean value at baseline for Hb was 8.9 g/dL (range, 7.4–11.4) and for Hb F was 1.11 g/dL (range, 0.15–3.33). Eight patients had data available both for Weeks 4 and 8. On Week 8, total Hb increased from baseline by a mean of 0.3 g/dL (range, −0.7 to 1.2) and Hb F increased by a mean of 0.14 g/dL (range, −0.19 to 0.42). The figure reports individual changes in Hb F from baseline to Weeks 4 (dark bars) and Week 8 (light bars), with “X” denoting the 4 patients on HU, and shows an increase in Hb F in 7 of 8 patients for that period. Enrollment is expected to be completed in August 2011 and updated results will be available at the meeting. In conclusion, the safety profile of HQK-1001 is consistent with results reported in prior studies and shows no overlapping toxicity with HU. Hb F is apparently increased in 7 of 8 patients with data available at Week 8, and this increase is seen both in patients receiving HU or not. Longer follow-up is needed to fully assess the safety of HQK-1001 and the extent of its effect on Hb F, total Hb, and SCD-related events. Disclosures: Aiello: HemaQuest Pharmaceuticals: Employment. Johnson:HemaQuest Pharmaceuticals: Employment. White:HemaQuest Pharmaceuticals: Consultancy. Ghalie:HemaQuest Pharmaceuticals: Employment.

Description: Abstract 4280 Beta thalassemia intermedia syndromes are serious conditions for which there is no satisfactory therapy to correct the underlying globin chain imbalance. Some agents that induce fetal globin gene expression have ameliorated anemia in thalassemia patients by reducing the imbalance in alpha: non-alpha globin synthesis, but none have been broadly accepted or are currently approved by regulatory authorities. HQK-1001 is an oral agent that targets the fetal globin gene promoter, thereby increasing fetal hemoglobin (HbF) expression. It has been well tolerated in single dose and multiple dose escalation clinical studies in healthy volunteers. We now report the results of a randomized, double blind, placebo-controlled, multiple ascending dose Phase I/II trial in 21 adult patients with beta thalassemia intermedia (BTI), including 14 with HbE/ß0 thalassemia and 7 with ß+/ß0 thalassemia (including 12 different beta globin gene mutations). Study medication was taken as a single daily dose for 8 weeks. Four ascending dose levels (10, 20, 30, and 40 mg/kg/day) were sequentially evaluated in 4 dose level cohorts after the preceding dose and schedule were determined safe by an independent and unblinded Safety Monitoring Committee. HQK-1001 was well-tolerated. Adverse events in treated subjects included headache, upper respiratory infection and nausea, but the rates of such events were not markedly different than those observed in the placebo-treated subjects. The 20 mg/kg dose was associated with a 10% mean increase above baseline in HbF, (p〈 0.001). Total hemoglobin (Hgb) increased by a mean of 1.1 gram/dL in 3 of 6 treated BTI patients with Mediterranean mutations. F-cells increased over the study period with maximal increases often observed 2 weeks following therapy. Doses higher than 20 mg/kg were not associated with the same magnitude of pharmacodynamic effects. These observations indicate that HQK-1001 is well-tolerated at doses associated with favorable pharmacodynamic effects on Hgb and HbF. These findings with brief treatment provide a rationale for conducting larger and longer studies in BTI patients. Disclosures: Fuchareon: HemaQuest Pharmaceuticals, Inc: Honoraria, Research Funding. Inati:HemaQuest Pharmaceuticals, Inc: Honoraria, Research Funding. Boosalis:HemaQuest Pharmaceuticals, Inc: Equity Ownership, Research Funding. Thein:HemaQuest Pharmaceuticals, Inc: Research Funding. Wallis:HemaQuest Pharmaceuticals: Consultancy, Equity Ownership. Bobbitt:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Patents & Royalties. Thomson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Johnson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Berenson:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Perrine:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Description: Background: Sickle cell disease (SCD) is an inherited genetic disorder that results in the formation of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, deforming erythrocytes and leading to chronic hemolysis, anemia and vaso-occlusion. Sickle cell nephropathy (SCN) is the term used to describe the renal complications of SCD. Renal vaso-occlusion and hemolysis contribute to the manifestations of SCN which include hyperfiltration and progressive renal impairment. Chronic kidney disease (CKD) is diagnosed if abnormalities in kidney structure or function are present for 〉3 months. The prevalence of CKD in patients with SCD increases with age, and ~12% of patients progress to end-stage renal disease (Gosmanova et al. J Investig Med 2014; Powars et al. Medicine 2005). There are no treatments approved for CKD caused by SCD. Standard of care (SoC) typically consists of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs) and/or hydroxyurea (HU). Evidence for the clinical effectiveness of ARBs and ACE inhibitors has been generated mainly from trials in other causes of kidney disease or short-term studies in SCD. P-selectin contributes to vaso-occlusion by mediating adhesion of sickled erythrocytes and leukocytes to the endothelium. Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin with high affinity and specificity. In SUSTAIN, crizanlizumab significantly reduced the median annual rate of vaso-occlusive crises compared with placebo (Ataga et al. N Engl J Med 2017). Preclinical data show P-selectin expression in the kidneys and upregulation in response to renal ischemia-reperfusion injury (Singbartl et al. FASEB J 2000; Zizzi et al. J Pediatr Surg 1997). Crizanlizumab may have a beneficial effect in patients with SCD and CKD by blocking P-selectin-mediated multicellular adhesion, reducing the effects of vaso-occlusion in the renal vasculature and slowing the decline in renal function. The aim of the STEADFAST study is to determine if crizanlizumab can slow the progression of CKD due to SCD (EUDRACT no. 2018-003608-38). Methods: Approximately 170 patients aged ≥16 years with CKD due to SCD will be enrolled. Eligible patients will have HbSS or HbSβ0-thalassemia genotypes, an estimated glomerular filtration rate (eGFR) ≥45 to ≤120 mL/min/1.73 m2, an albumin-to-creatinine ratio (ACR) ≥100 to

Description: Background: There is a significant unmet need for treatments to reduce vaso-occlusive crises (VOCs) in sickle cell disease (SCD). Until recently, the only pharmacological treatment approved for reduction of VOCs was hydroxyurea (hydroxycarbamide), and is recommended for children ≥9 months old with SCD. L-glutamine is approved for the reduction of acute complications of SCD in children ≥5 years old, although symptoms can start as early as 5 months of age. Inhibition of platelet activation has been proposed as a potential therapeutic option for SCD. The rationale for the use of antiplatelet therapies in SCD management is based on evidence that platelets participate in the vaso-occlusive process and that platelet activation correlates with the frequency of pain episodes (Ataga et al, 2012). Platelets are activated during the non-crisis steady state (Lee et al, 2006). The antiplatelet drug ticlopidine, which has a similar mechanism of action as ticagrelor (prevention of adenosine diphosphate [ADP]-mediated platelet activation), significantly reduced the frequency of VOCs in patients with SCD (Cabannes et al, 1984). In the phase III DOVE study in pediatric patients, the platelet inhibitor prasugrel was shown to result in a numerical reduction in VOC events with fewer painful crises in the prasugrel group (66%) versus placebo (72%); however, the differences versus placebo did not reach statistical significance (Heeney et al, 2016). Of note is that the prasugrel doses used in DOVE only resulted in a mean platelet inhibition of ~20% (Jakubowski et al, 2017). The low platelet inhibition may have contributed to the lack of efficacy in this study (Heeney et al, 2016). Ticagrelor is an oral, direct-acting, selective, reversibly-binding P2Y12 receptor antagonist that prevents ADP-mediated platelet activation and aggregation. Ticagrelor was approved in 2010 to reduce the rate of cardiovascular death, myocardial infarction, and stroke in adult patients with acute coronary syndromes, and is currently approved in 〉100 countries. A program is currently ongoing to assess the potential therapeutic benefits of ticagrelor in reducing the occurrence of VOCs in children with SCD. A phase III study (HESTIA3; NCT03615924) is underway to evaluate the efficacy of ticagrelor in reducing the rate of VOCs, as well as the safety and tolerability of ticagrelor versus placebo in SCD pediatric patients 2 to

Description: Background: Sickle cell disease (SCD) is one of the most prevalent hemoglobinopathies in Lebanon, where 0.1% of the population are affected by the disease, with the highest prevalence in North Lebanon. SCD burden has not been well characterized in this patient population. Moreover, there is limited understanding of the factors associated with complications of SCD. We hereby report on characteristics, complications, treatments and survival of a SCD cohort treated at a comprehensive SCD referral clinic in North Lebanon. Methods: Data were extracted from the health records and electronic registry of 335 SCD patients treated at the comprehensive SCD clinic of Nini hospital, Tripoli, North Lebanon between 2009 and 2019. The study population consisted of referred and newly diagnosed patients. Patients were considered to be newly diagnosed with SCD if there was a gap of ≤ 60 days between SCD diagnosis date and their first clinic visit date. Patients were regularly seen in the clinic at intervals ranging from every 2 months to 1 year depending on their age and disease severity. Patient characteristics, complications, treatment choices, and mortality were evaluated during follow-up. Follow-up was defined as the time between SCD diagnosis and last visit to the clinic. Complications included vaso-occlusive crisis (VOC), acute splenic sequestration (ASS), stroke, dactylitis, joint necrosis, priapism, leg ulcers, sepsis, iron overload and mortality. VOC events, defined as the composite of pain and/or acute chest syndrome (ACS), were only reported if they resulted in a hospitalization. Since history of VOC events was not well documented among referred patients, VOC events were assessed among patients newly diagnosed at the clinic. Results: The mean age of the study population at SCD diagnosis was 2.9 years (standard deviation [SD]: 4.3), with 73.1% of patients diagnosed within 3 years of age. Mean age at first visit to the clinic was 8.6 years (SD 10.0). 159 (47.5%) patients were female. The most common genotypes were Hemoglobin SS (233 [69.6%]), Hemoglobin Beta-0 Thalassemia (62 [18.5%]), and Hemoglobin Beta + thalassemia (27 [8.1%]). The mean number of follow up years between SCD diagnosis date and latest visit date to the clinic was 13.7 (SD: 10.5). 132 (39.4%) patients were newly diagnosed at the time of their first visit to the clinic. The most frequently encountered SCD clinical events were pain (189 [56.4%]) followed by ACS (135 [40.3%]), ASS (115 [34.3%]) and joint necrosis (55 [16.4%]). The incidence of stroke, pulmonary hypertension, priapism, leg ulcers and sepsis was low (3.3%, 4.2%, 6.0%, 3.0% and 3.9%). Persistent splenomegaly beyond 6 years was seen in 57 (17%) patients, 36 (63.2%) of these patients were of SS genotype. 276 (82.4%) patients required at least one hospitalization during their follow-up. Among newly diagnosed patients, 63% experienced at least one VOC event that led to a hospitalization with a mean of 0.4 (SD: 0.6) hospitalized VOC events per patient per year. 15 (4.5%) patients died during follow-up. The most common cause of death was stroke (3 [20%]). 84 (25.1%) and 76 (22.7%) patients underwent a cholecystectomy and surgical splenectomy respectively, and 30 (9.0%) patients underwent both. 236 (70.5%) patients were treated with Hydroxyurea. The mean age at introduction of Hydroxyurea was 11.5 years (SD: 10.1) and median starting dose was 15.2 mgs/kg/day. 281 (84%) patients received at least one blood transfusion during their follow-up. 37 (11.0%) patients received iron chelation during their follow up. 3 (0.9%) patients underwent bone marrow transplant and were cured of their disease. Conclusion: This first SCD study from North Lebanon demonstrates that SCD burden in North Lebanon is significant. Despite the high disease burden and the low community resources in this region, survival rate of this SCD patient population is relatively high. This can be attributed to the young age at diagnosis, the close comprehensive follow-up and the regular parent/patient education. The low rate of stroke, priapism and leg ulcers in this population warrants further investigation via disease associated markers and genetic determinants. As for priapism, it may be underreported due to social stigma in a conservative country as Lebanon. Noteworthy, Iron overload is under recognized and sub optimally treated. The association between specific risk factors and disease complications will be further addressed. Disclosures Inati: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Global Blood Therapeutics: Research Funding. Kanakamedala:Novartis: Consultancy; Genesis Research: Employment. Pilipovic:Novartis Pharma AG: Employment, Equity Ownership. Sabah:Novartis: Employment.

Description: Abstract 904 Background: As a result of previous transfusions, β-thalassemia major (TM) patients who have undergone curative hematopoietic stem cell transplantation (HSCT) are at increased risk of iron overload. There are, however, limited data on iron removal in such patients with either phlebotomy (PHL) or iron chelation. The aim of this study was to compare the efficacy, safety and convenience of the oral iron chelator deferasirox (DFX; Exjade®) with PHL for the treatment of iron overload in children with TM following HSCT, over a 1-year period. Methods: LB03T is a prospective, randomized trial enrolling children with TM aged 2-3 mg Fe/g dry weight [dw]). Eligible patients were randomized to PHL (6 mL/kg blood/2 weeks) or DFX (10 mg/kg/day starting dose; 5 mg adjustments up to 20 mg/kg/day were permitted). One of the primary endpoints was change in LIC assessed using magnetic resonance imaging techniques. Changes in serum ferritin levels, hemoglobin (Hb), total iron binding capacity (TIBC), non-transferrin-bound iron (NTBI), adverse events (AEs) and compliance with study treatment (PHL: ratio of performed:planned; DFX: tablet count) were also assessed. Convenience of treatment was evaluated using parents' responses to pre-prepared questions. Results: 27 patients were randomized to DFX or PHL; one patient randomized to PHL refused treatment, hence 12 patients received DFX and 14 received PHL. Mean age was 12.4 yrs and 53.8% were male. Patients were followed up for a mean of 12.0 months. 2 and 5 patients had DFX dose increases to 15 and 20 mg/kg/day, respectively. Mean DFX dose at last visit was 11.0 and 18.1 ng/mL in the LIC≤7 and LIC〉7 groups, respectively. Median serum ferritin was significantly reduced from baseline over 12 months with DFX (–497.5 ng/mL, P=0.004 vs baseline) and PHL (–901.8 ng/mL, P

Description: Abstract 5505 Introduction Bone marrow transplantation (BMT) represents the only curative modality for β-Thalassemia Major (β–TM). Best results are achieved in regularly transfused and chelated pediatric patients. Outcome of BMT in 36 Lebanese children who received treatment in the Mediterranean Institute of Hematology (IME) centers in Italy is presented. Methods 36 children with β–TM treated at Chronic Care Center, Lebanon underwent BMT from HLA compatible donors in IME centers.  Each was assigned a Pesaro risk category and underwent a percutaneous liver biopsy before BMT. Conditioning regimen consisted of busulfan, cyclophosphamide ± Thiotepa and ATG. GvHD prophylaxis included cyclosporine A, methotrexate and prednisolone. Engraftment was evaluated by fluorescence in situ hybridization. Transplant related mortality (TRM) and other complications were calculated as cumulative incidence. Analyses were performed using R software. Results 36 hepatitis B and C negative children with β –TM (M/F 1:l),  median age 8.5 years, underwent BMT from HLA identical donors. The most common β-globin mutation was homozygous IVS1.110 (39.29%). 20.5%, 55.9% and 23.5% had Pesaro risk class 1, 2 and 3, respectively.  Mean injected CD34+ cells, total nucleated cells and CD3+ cells/recipient  were 10.9x106 /Kg,  8.69x108/Kg and 66.3x106 /Kg. Absolute neutrophil count 〉0.5 x109 and platelet count 〉20 x 109 were reached in all patients within a mean of +19.44±4 and +19.15 ±6.5 days. Regular chimerism surveillance  showed complete engraftment in 35/36 children (97.3%)  up till+ 4.2 years median follow up. 1/36 (2.7%) had partial engraftment but continued to be transfusion independent with a mean Hb of 9g/dcl for +1155 days. Immune reconstitution was seen in all patients by + 12 -18 months. At a median follow up of + 6.20 years, 32/36 (89%) of children are alive and transfusion independent. Among those who died (11%), 1 had multi organ failure, 2 had grade 4 acute GvHD and 1 had fulminant interstitial pneumonitis.  47% had acute GvHD which was not correlated with donor relation, conditioning regimen, and pre-BMT hepatomegaly, splenomegaly and transfusion frequency. 8/36 (22%) had grade 2 to 4 acute GvHD of which 75% resolved on treatment while 25% (all grade 4) were fatal. 9/32 (28%) surviving children had chronic GvHD completely resolved on treatment and not correlated with  any recipient, donor or treatment feature.  Other transplant related complications included CMV reactivation, sepsis, EBV and candida infections, hemorrhagic cystitis, cerebral toxoplasmosis, tuberculosis and transient cyclosporine  related renal and neurotoxicity, all completely resolved on treatment. Late effects of transplant were monitored in 27 children.  Iron overload data utilizing magnetic resonance imaging at + 3.1 year median follow up showed that mean baseline LIC for 27 patients was 11.3 mg Fe/g dw but ranged as high as 36.6 mg Fe/g dw. Median serum ferritin was 1255 ng/mL, with a maximum of 5884 ng/mL.  9/27 (33.3%) children had significant iron overload defined as SF 〉2500 ng/ml, or LIC 〉15 mg Fe/g dw, or T2*

Description: Introduction Hereditary spherocytosis (HS), the most common cause of inherited chronic hemolysis in Northern Europe and North America, is characterized by a wide variety of clinical features, ranging from an asymptomatic condition to a fulminant hemolytic anemia. Guidelines regarding the management and diagnosis of HS have been updated in 2012. Few reports exist on HS prevalence and related molecular abnormalities in Mediterranean populations. The prevalence and features of HS in Lebanon have not yet been reported. The aim of this study is to determine demographic, clinical, hematological and therapeutic features as well as outcome of a group of Lebanese patients with HS. Methods This is a retrospective hospital-based surveillance study conducted at 4 centers in Northern Lebanon and Central Beirut. Data was collected from archived files on 31 patients between May 2012 and May 2013 and included patients’ demographics, clinical presentation, diagnostic laboratory tests, treatment modalities and outcome. Analysis was conducted using SPSS 19, and t-test was used to compare two groups. We also conducted an Analysis of Variances where we included demographic variables that were different between the two groups as covariates (ANCOVA) in order to look for group effect. Statistical significance was set at p