All Patients With Sickle Cell Disease Should Be Treated With Hydroxyurea

Transcription

1 All Patients With Sickle Cell Disease Should Be Treated With Hydroxyurea Miguel R. Abboud MD Department of Pediatrics and Adolescent Medicine American University of Beirut, Beirut, Lebanon

2 Introduction Sickle cell disease is a single gene defect that leads to multi-organ damage The clinical manifestations are often heterogeneous even among siblings and twins Modifiers and biomarkers of the disease process (genetic and physiologic factors) such as HbF and TCD as well as response to treatment with hydroxyurea will be discussed.

3 Pathophysiology of SCD β-globin gene Glutamic acid A G G HbS T Valine Low oxygen tension Deoxygenated Hb polymers Haemolysis Anaemia, jaundice, gallstones, leg ulcers, priapism, pulmonary hypertension, cardiomegaly, failure to thrive Sickle cell Vaso-occlusion Pain, ACS, stroke, joint necrosis, functional hyposplenism and autosplenectomy, increased infections, multi-organ failure ACS = acute chest syndrome; HbS = sickle cell haemoglobin; SCD = sickle cell disease.

4 Consequences of sickling Vaso-occlusion ischemia reperfusion injury K+ loss RBC dehydration Adhesion to WBCs, endothelium Hb polymerization Membrane damage Lipid peroxidation ROS, XO Sickled RBCs Increased inflammation NF-kB activation Adhesive proteins Inflammatory cytokines Activation of WBCs, platelets Hemolysis NO scavenging Endothelial dysfunction PS exposure Activation of coagulation TF Thrombin Protein C and S Platelet activation Natarajan K et al. In: Williams Hematology, 8th edition; 2010; Chapter 48. Hb = hemoglobin; NF- kb = nuclear factor kappa B; NO = nitric oxide; PS = protein S; RBC = red blood cell; ROS = reactive oxygen species; TF = tissue factor; WBC = white blood cell; XO = xanthine oxidase

5 Complications of SCD in children Polymerization of deoxy-hbs Endothelial dysfunction Age (years) Bacteraemia Pain ACS highly variable ASS Stroke Chronic organ damage? ASS = acute splenic sequestration. Castro O, et al. Blood. 1994;84: Gill FM, et al. Blood. 1995;86: Ohene-Frempong K, et al. Blood. 1998;91:

6 Potential modifiers of disease severity Neutrophils/ inflammation Adhesion molecules Red blood cells HbF α-thalassaemia Endothelium NO/ET1 ET1 = endothelin-1; HbF = fetal haemoglobin; NO = nitric oxide. Adapted from Stuart MJ, Nagel RL. Lancet. 2004;364:

7 Survival in paediatric patients has significantly improved 1.0 Fraction surviving Follow-up (years) Dallas London Dallas CSSCD Infant Jamaica Jamaica Quinn CT, et al. Blood. 2010;115:

8 Causes of death in children with SCD Year (range) Country Incidence Causes Gill USA 1.1/100 pt-yr 11 sepsis (9 S.pn), 2 ASS, 1 CVA Thomas France (Paris) 0.29%/yr 15 sepsis (8 S.pn), 3 ASS, 3 CVA Quinn USA (Texas) 0.59/100 pt-yr 5 sepsis (4 S.pn), 3 ACS, 2 multi-organ failure, 1 CVA, 1 myocardial infarct Quinn USA (Texas) 0.52/100 pt-yr 5 ACS, 4 multi-organ failure, 4 S.pn sepsis CVA = cerebrovascular accident; pt-yr = patient years; S.pn = Streptococcus pneumoniae. Gill FM, et al. Blood. 1995;86: Thomas C, et al. Arch Pediatr. 1996;3: Quinn CT, et al. Blood. 2004;103: Quinn CT, et al. Blood. [Epub ahead of print 2010 Mar 1].

9 Causes for deaths in children screened at birth in recent series Telfer Quinn Bernaudin UK, USA, N patients France N deaths Pneumococcal sepsis CVA Ac.spl.sequest 0 0 0

10 Early diagnosis is mandatory In regions with high prevalence of the trait, or high flow of emigration from regions with a high prevalence Universal neonatal screening In regions with low prevalence of the trait, or low flow of emigration from those regions - infants originating from at risk regions - mothers early in pregnancy - adolescents Prenatal diagnosis

11 Neonatal screening This image cannot currently be displayed. IEF Penicillin Immunization Folic acid Confirmatory tests Expertise centre Education Network of trained physicians

12 City/country Neonatal screening for SCD in Europe N babies affected with SCD/screened babies N SS /screened babies N SC/screened babies N S/thal/screened babies N with S trait ;with C trait/screened babies Reference Brussels/Belgium 1/1954 1/ / /65; 1/508 Gulbis, 2009 Liege/Belgium 1/1714 1/5998 1/ /65;1/387 Gulbis, 2009 Madrid/Spain 1/6914 Manu-Pereira, 2009 England London/England 1/2000 (hemoglobin E diseases included) 1/549(hemoglobin E disease included) Streetly, 2009 Streetly, 2009 France 1/2065 Bardakdjian-Michau, 2009 Ferrara/Italy 0 1/135 ;1/541 Ballardini, 2012

13 Cartograms of the estimated number of newborns with SCA per country. Piel FB, Hay SI, Gupta S, Weatherall DJ, et al. (2013) Global Burden of Sickle Cell Anaemia in Children under Five, : Modelling Based on Demographics, Excess Mortality, and Interventions. PLoS Med 10(7): e doi: /journal.pmed Systematic screening Experimental screening

14 Role of hydroxyurea in SCD Predictors of severity Evidence Based Effects of hydroxyurea on painful crises pulmonary complications ACS Mortality Strokes Toxicity and complications Comparisons

15 Life expectancy of patients with SCD in the USA in Probability of survival Females with SS Males with SS Black females Black males Probability of survival Females with SC Males with SC Probability of survival HbF 8.6% HbF > 8.6% A Age (years) B Age (years) C Age (years) SS = sickle cell anaemia; SC = sickle cell haemoglobin C disease. Platt OS, et al. N Engl J Med. 1994;330:

16 Risk Factors for Early Death in Patients with Sickle Cell Anemia Who Were 20 Years of Age or Older Platt, O. S. et al. N Engl J Med 1994;330:

17 Hydroxyurea therapy counters the established risk factors for earlier death: decreases the rate of ACS, decreases WBC, increases Hb F level

18 Hydroxyurea A cytotoxic, antimetabolic and antineoplastic agent Potent inhibitor of ribonucleotide reductase An S-phase-specific agent, inhibits DNA synthesis and eventually cellular cytotoxicity

19 Clinical effects of hydroxyurea Illustration ciurtesy of Alice Y. Chen

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21 Peripheral blood smear morphology in sickle cell anemia and response to hydroxyurea therapy

22 Multicenter study of hydroxyurea in adults with SCA: MSH trial Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia» Charache et al., NEJM 332:1317, 1995 Methods: RCT of HU in Hb SS disease. Maximum tolerated dose (maximum dose of 35 mg/kg) 152 HU/147 placebo patients Mean follow-up: 21 months

23 Results of the MSH trial in SCA Variable Hydroxyurea Placebo Annual pain episodes 2.5 episodes/yr 4.5 episodes/yr p<0.001 Median time to 1st crisis 3.0 months 1.5 months P = 0.01 Median time to 2nd crisis 8.8 months 4.6 months p<0.001 Acute chest syndrome (rate per year) 16.5% 35% p<0.001 Transfusions 48 patients 73 patients p<0.001 Hemoglobin F% 75 th percentile 25 th percentile NA Charache et al., NEJM 332:1317, 1995

24 Impact of hydroxyurea on clinical events in the BABYHUG trial Infants with SCA (beginning at 9-18 months of age) Randomized to HU (20 mg/kg/d) or placebo n=193, 374 patient-years of on-study observation Hydroxyurea was associated with - lower rates of initial and recurrent episodes of pain, dactylitis, ACS and hospitalization - infants who were asymptomatic at enrollment had similar clinical benefit with hydroxyurea. - well tolerated, no increased toxicity Thornburg et al. Blood. 2012;120(22):

25 Given hydroxyuea s impact on established mortality risk factors ACS, WBC, and Hb F we expect hydroxyurea therapy to decrease rate of death

26 Effect of hydroxyurea on mortality in adult sickle cell anemia in the MSH trial After 9 years of follow-up: - Mortality was associated with HbF concentration, rate of acute pain episodes and acute chest syndrome - Hydroxyurea was associated with a 40% reduction in mortality (P = 0.04) After 17.5 years of follow-up: % of cohort died (4.4/100 person yrs) % in patients who took no hydroxyurea Steinberg et al., AJH 85: , 2010

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28 MSH study: cumulative mortality in patients with sickle cell anaemia Cumulative death rate (%) A Placebo Hydroxyurea p = 0.35 B Haemoglobin F < 0.50 g/dl 0.50 g/dl p = 0.03 C Neutrophil count < 5,000/mm 3 5,000/mm 3 p = Years since randomization Years since randomization Years since randomization D Cumulative death rate (%) Reciculocyte count < 250,000/mm 3 Haemoglobin < 9 g/dl Haemoglobin 9 g/dl Reciculocyte count 250,000/mm 3 Haemoglobin < 9 g/dl Haemoglobin 9 g/dl E Acute chest syndrome episodes 1 None F Painful episodes 3/y < 3/y p = p = 0.02 p = Years since randomization Years since randomization Years since randomization Steinberg MH, et al. J Am Med Assoc. 2003;289:

29 The risk and benfits of long-term use of HU in SCA 17.5 year follow up Amer J. Hematology 010 Jun;85(6): sites, 1/1992-6/1994 Follow up through 8/2009 <5 yr HU No HU 5-10 yr HU yr HU >15 yr HU

30 Effect of hydroxyurea on morbidity and mortality in SCD: results of a 17-year, single-center trial (LaSHS) Greece Overall survival Other outcomes Survival benefit was across all phenotypes (ages 16+) The HU group had reduction in the frequency of acute pain, transfusion requirements, hospital admissions, and incidence of ACS. Baseline HbF and change in LDH were predictive of OS Voskaridou et al, Blood Mar 25;115(12):

31 Causes of death in Athens cohort Cause of death HU patients (13/131 = 9.9%) Non-HU patients (49/199 = 24.6%) Liver dysfunction 1 10 Pulmonary hypertension 8 8 Stroke 3 10 Sudden death 3 5 Vaso-occlusion crisis 1 6 Acute chest syndrome 1 5 Sepsis 1 1 Heart failure 2 2 Intervention 1 2 Blood. 2010;115:

32 Survival Among Children and Adults with SCD in Belgium: Benefit From HU Treatment 469 patients 5110 pt. years 185 HU 90 HSCT 24 Chronic Transfusions 170 No Therapy HU vs HSCT 99.4% vs 93.8% (p= 0.01) HU Vs NT 99.4% vs 95.4% (p=0.04) Pediatr Blood Cancer 2015;62:

33 The effect of hydroxcarbamide therapy on survival of children with sickle cell disease: Brazilian cohort Other outcomes Ages 3-18 years with SCD met disease severity criteria. Median dose of 20.8 mg/kg/d Compared to untreated pts, those on HU had improved lab indices, less severity, and overall survival (p=0.01). Lobo et al., BJH Jun;161(6): ,

34 Hydroxyurea Therapy As an Alternative to Transfusions for Primary Stroke Prevention in Children with Sickle Cell Anemia In the multicenter Phase III TWiTCH trial, which treated children with SCA and abnormal TCD velocities but without severe MRA vasculopathy Hydroxyurea at MTD was non-inferior and possibly superior to chronic transfusions for maintaining TCD velocities.

35 Benefits and Risks of HU Benefits Decrease rate of pain acute chest syndrome Improved anemia Reduction in hospitalizations Improved quality of life* Survival advantage* Decreased TCD velocity* Oral medication Risks Myelosuppression Increased risk of fetal abnormalities Not curative, does not reverse chronic end-organ damage Male Fertility? Long term use? Large prospective observational study of 1638 patients with PCV Did not show increased risk of leukemia attributable to hydroxyurea

36 Final TCD velocities (mean ± standard error) in the transfusion and hydroxyurea arms were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively Intention-to-treat analysis: p-value for non-inferiority = 8.82 x Post-hoc analysis the p-value for superiority = Among 29 new neurological events, all centrally adjudicated by masked reviewers, there were no strokes but 6 transient ischemic attacks (3 in each arm). In the multicenter Phase III TWiTCH trial, which treated children with SCA and abnormal TCD velocities but without severe MRA vasculopathy Hydroxyurea at MTD was non-inferior and possibly superior to chronic transfusions for maintaining TCD velocities.

37 Intervention and outcome of 43 survivors of first clinical stroke in Jamaica 1st stroke N = 43 HU n = 10 No HU n = 33 No re-stroke n = 9 Re-stroke* n = 1 (10%) No re-stroke n = 13 Re-stroke* n = 20 (60.6%) Died n = 1 HU, n = 3 1 re-stroke *HR 9.4 (95% CI ); p <0.03 No HU, n = 16 7 re-stroke (2 died) Ali SB, et al. Am J Hematol. 2011;86:

38 Figure 2. Cartograms of the estimated number of newborns with SCA per country. Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN (2013) Global Burden of Sickle Cell Anaemia in Children under Five, : Modelling Based on Demographics, Excess Mortality, and Interventions. PLoS Med 10(7): e doi: /journal.pmed

39 Figure 3. Country ranking based on estimated number of newborns with SCA in 2010 and Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN (2013) Global Burden of Sickle Cell Anaemia in Children under Five, : Modelling Based on Demographics, Excess Mortality, and Interventions. PLoS Med 10(7): e doi: /journal.pmed

40 Figure 5. Projections of estimated newborns with SCA between 2010 and Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN (2013) Global Burden of Sickle Cell Anaemia in Children under Five, : Modelling Based on Demographics, Excess Mortality, and Interventions. PLoS Med 10(7): e doi: /journal.pmed

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42 Low and fixed dose of hydroxyurea is effective and safe in patients with HbSβ+ thalassemia with IVS1-5(G C) mutation Pediatric Blood & Cancer Volume 62, Issue 6, pages , 24 DEC 2014 DOI: /pbc

43 Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial Pediatric Blood & Cancer Volume 63, Issue 1, pages , 14 AUG 2015 DOI: /pbc

44 Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial Pediatric Blood & Cancer Volume 63, Issue 1, pages , 14 AUG 2015 DOI: /pbc

45 Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial Pediatric Blood & Cancer Volume 63, Issue 1, pages , 14 AUG 2015 DOI: /pbc

46 Problems and Advantages How to ensure compliance in large numbers of patients? No liquid formulation How to provide drug and monitor in low income countries where resources are limited? Inexpensive 1USD a day Underutilized and has No GVHD No iron overload No major toxicity Use hydroxyurea in all Patients

47 Neonatal screening and follow up IEF Penicillin Immunization Folic acid Confirmatory tests Expertise centre Education Network of trained physicians HU

48 Dactylitis

49 Use hydroxyurea in all Patients Acute vaso-occlusive complications recurrent painful events ACS Frequent hospitalizations Laboratory markers of severity low haemoglobin low fetal haemoglobin elevated WBC elevated LDH

50 Ware RE. Blood. [Epub ahead of print 2010 Mar 11]. Hydroxyurea in SCD: multiple mechanisms of action

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52 Hydroxyurea Potential to increase HbF Have salutary effects on the adverse risk factors Phase 3 randomized trial 299 adults, 21 centres Decreased rate of painful crises by 50% Decreased rates of hospitalization for pain or ACS and decreased numbers transfusions Led to FDA approval of hydroxyurea ACS = acute chest syndrome; FDA = US Food and Drug Administration. Charache S, et al. N Engl J Med. 1995; 332:

53 Probability of 10-year overall survival according to molecular subtypes of SCD Voskaridou, E. et al. Blood 2010;115:

54 Causes of death in Athens cohort Cause of death HU patients (13/131 = 9.9%) Non-HU patients (49/199 = 24.6%) Liver dysfunction 1 10 Pulmonary hypertension 8 8 Stroke 3 10 Sudden death 3 5 Vaso-occlusion crisis 1 6 Acute chest syndrome 1 5 Sepsis 1 1 Heart failure 2 2 Intervention 1 2 Voskaridou E, et al. Blood. 2010;115:

55 Fetal haemoglobin levels remain close to 20% during extended hydroxyurea therapy in infants with SCA 35 Patients receiving extended HU therapy (mean values ± SD values for HbF) Untreated American children with SCA Jamaican children with SCA HbF% Years on HU HbF = fetal haemoglobin; HU = Hankins JS, et al. Blood. 2005;106:

56 Long-term trial of hydroxyurea in children Hospitalizations/pt-yr Days in hospital/pt-yr Number of events Before Years Gulbis B, et al. Blood. 2005;105:

57 Wang W et al Lancet :1663 Slides courtesy of Dr. W Wang BABY HUG - Eligibility Inclusion criteria: Diagnosis of HbSS or HbSβ thalassemia Age 9-18 months (at randomization) No severity requirement Exclusion criteria: Recent transfusion Height, weight, or head circumference < 5 th % Mental Developmental Index < 70 Abnormal velocity on TCD

58 BABY HUG - Efficacy Endpoints Primary Spleen qual. uptake on radionuclide L/S scan Kidney - GFR using 99m Tc DTPA clearance Secondary Spleen - pit cells, Howell-Jolly bodies,s:l counts Kidney - urine concentrating ability CNS - TCD velocities Lungs O 2 saturation Hematologic changes CBC,HbF Clinical events pain, ACS, etc. Wang W et al Lancet :1663 Slides courtesy of Dr. W Wang

59 Cumulative Probability of Adverse Events

60 Clinical Outcomes: BABY HUG compared with MSH BABY HUG MSH HU PL p HU PL p n pain /y 4.5/y <0.001 ACS <0.001 dactylitis <0.001 hospitalization* /y 2.4/y transfusion data indicate no. of episodes *in BABY HUG, all hospitalizations; in MSH, hospitalization for pain only in BABY HUG, no. of transfusions; in MSH, no. of pts. receiving transfusion

61 BABY HUG Exit Data for Organ Function Hydroxyurea Placebo P 1 P 2 n Spleen scan: N/ /A 10/53/22 8/46/ better/same/worse 13/53/19 6/48/ S:L counts/pixel (Δ) Pit cells >3.5% (%) HJB >300/10 6 RBC (%) DTPA GFR (ml/min/1.73m 2 ) Urine osmolality TCD velocity (cm/sec) <0.003 TCD abnl./conditional 1/10 3/ Bayley MDI Bayley MDI < Height (cm) Weight (kg) O 2 saturation (%) P 1 = comparison of 2 groups at exit P 2 = comparison of differences between [baseline exit] differences

62 The effect of hydroxcarbamide therapy on survival of children with sickle cell disease: Brazilian cohort Ages 3-18 yrs severity criteria: 1 episode of ACS. Higher overall survival (p=0.01) 99.5% vs 94.5% 1760 pts 267 received HU 38 deaths: 36 not on HU 1on HU Causes: 17 due to ACS 1 st episode 13 due to infection 4 due to stroke Lobo et al., BJH Jun;161(6): ,

63 Prophylaxis of recurrent stroke: why not use hydroxyurea? Chronic transfusions prospectively discontinued in 35 children with stroke started on HU and phlebotomies to reduce iron overload After a mean of 42 (range 3 104) months 7 patients (20%) had recurrent ischaemic strokes Recurrent stroke incidence lower in a subgroup who started HU before transfusions were stopped Regimen may be effective in preventing stroke recurrence This question was addressed in a new prospective randomized trial known as SWiTCH SWiTCH = stroke with transfusions changing to hydroxyurea. Ware RE, et al. J Pediatr. 2004;145:

64 Aims and study design Aim: to compare 30 months of hydroxyurea and phlebotomy (alternative) with transfusions and deferasirox (standard) for the prevention of secondary stroke and reduction of transfusional iron overload 161 paediatric patients with sickle cell anaemia (83 male, 78 female), documented stroke and iron overload enrolled in SWiTCH (US10) 134 patients randomized 1:1 Alternative arm 67 patients Hydroxyurea + phlebotomy Standard arm 67 patients Transfusions + deferasirox Prediction: increased occurrence of recurrent stroke events in alternative arm counter-balanced by better management of iron overload with phlebotomy Ware RE, Helms RW. Blood :

65 Results: stroke recurrence rate The difference in stroke rates between the two arms was greater than expected Transfusions + deferasirox Treatment arm Hydroxyurea + phlebotomy Stroke incidence 0/66 (0%) 7/67 (10%) Many patients had severe vasculopathy Composite end point used Ware RE, Helms RW. Blood. 2012;119:

66 Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial American Journal of Hematology 17 NOV 2015 DOI: /ajh.24198

67 Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial American Journal of Hematology 17 NOV 2015 DOI: /ajh

68 Effect on Renal Function Baby HUG 193 infants mean age 13.8 months randomized to HU 20 mg/kg or placebo for 24 months No difference in GFR between the two groups both higher than normal At study entry 22% of infants hyposthenuria At 3 years infants on HU had higher urine osmolality495 vs 452 and (p=0.007) after water deprivation 50% on HU had osmolality >500 vs 34% on placebo (0.03) they had higher fetal hemoglobin Alvarez et al PBC 2012 E pub

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70 Effect of hydroxyurea therapy on pneumococcal pneumonia Mean overall survival of SCA mice HU Saline Mock-transpl. mice receiving saline Survival of non-transplanted WT mice (C57/bl6) HU Saline Survival (%) * * Survival (%) Survival time (hours) Survival time (hours) Lebensburger JD, et al. Blood. 2012;119:

71 Baseline expression of E-selectin (represented by the frequency of E in each panel) affects the outcome of bacterial pneumonia challenge with Streptococcus pneumoniae Bacterial infection & inflammation Baseline Normal Normal WBC & E-selectin Clears bacteria Limited lung damage Sickle High WBC & E-selectin Difficulty clearing bacteria Extensive lung damage Bacteria leakage into blood Sickle with hydroxyurea Clears bacteria Limited lung damage Near-normal WBC & E-selectin Sickle E-selectin -/- Clears bacteria Limited lung damage Near-normal WBC Hsu LL. Blood. 2012;119:

72 Ware R, et al. Hematology Am Soc Hematol Educ Program. Effectiveness of hydroxyurea in SCD Criterion Outcome Level of evidence Fetal haemoglobin Increased High Pain crises Decreased High Hospitalizations Decreased High Transfusions Decreased High ACS Decreased High Mortality Decreased Low Neurological events Decreased Insufficient

73 Ware R, et al. Hematology Am Soc Hematol Educ Program. Effectiveness of hydroxyurea in SCD Criterion Outcome Level of evidence Fetal haemoglobin Increased High Pain crises Decreased High Hospitalizations Decreased High Transfusions Decreased High ACS Decreased High Mortality Decreased Low Neurological events Decreased Insufficient

74 Ware RE. Blood : ]. Why use hydroxyurea at MTD? Year Patients (N) Age (years) MTD Dose (mg/kg/d) Treatment (years) Hb (g/dl) MCV (fl) HbF (%) WBC (x 10 9 /L) ANC (x 10 9 /L) Ref Yes Yes Yes Yes NA Yes NA NA Yes NA Yes Unpub No ~ NA No ~ NA No ~ NA No ~ NA

75 Toxicity of hydroxyurea Toxicity Outcome Level of evidence Leg ulcers Comparable High Leukaemia Comparable Low Other cancers Comparable Low Spermatogenesis Defects Insufficient Pregnancy Comparable Insufficient Ware R, et al. Hematology Am Soc Hematol Educ Program. 2009:62-9.

76 Treatment studies in SCD There was 1 randomized trial of hydroxyurea in adults with SCD Many non-randomized trials of hydroxyurea in children No randomized trials of transfusions in SCD outside STOP and the Preoperative Transfusion Study Acute Chest Study not randomized No randomized HSCT trials

77 From: Management of Sickle Cell Disease: Summary of the 2014 Evidence-Based Report by Expert Panel Members JAMA. 2014;312(10): doi: /jama Date of download: 9/14/2014 Copyright 2014 American Medical Association. All rights reserved.

78 Concentration-time profiles of hydroxyurea in young patients with SCA Shown are representative examples of Fast phenotype with peak concentration at minutes (59% of patients) and the Slow phenotype with Cmax at either 60 or 120 minutes (41% of patients) Ware R E et al. Blood 2011;118:

79 Figure 1. Multiple mechanisms of action byhydroxyurea for SCA. (1) Fetal hemoglobin induction through soluble guanylyl cyclase activation and altered erythroid kinetics; (2) lower neutrophil and reticulocyte counts from ribonucleotide reductase inhibition and marrow cytotoxicity; (3) decreased adhesiveness and improved rheology of circulating neutrophils and reticulocytes; (4) reduced hemolysis through improved erythrocyte hydration, macrocytosis, and reduced intracellular sickling; and (5) nitric oxide (NO) release with potential local vasodilatation and improved vascular response. Illustration courtesy of Alice Y. Chen. Published in: Patrick T McGann; Russell E Ware; Expert Opinion on Drug Safety Ahead of Print Copyright 2015 Informa UK, Ltd.

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81 Figure 2. Peripheral blood smear changes with hydroxyurea therapy. Panel A illustrates the severe anemia and frequent irreversibly sickled erythrocytes commonly observed in untreated patients with SCA. Panel B demonstrates the improvement in anemia and increases in both the size and hemoglobin content of erythrocytes while on hydroxyurea therapy. Published in: Patrick T McGann; Russell E Ware; Expert Opinion on Drug Safety 2015, 14, DOI: / Copyright 2015 Taylor & Francis

82 Selectins mediate WBC adhesion, rolling Selectins are expressed on endothelial cells, platelets, and leukocytes, as well as other cell types 1 P-selectin and E-selectin mediate rolling and tethering of blood cells to the endothelium 2 may initiate vaso-occlusion in the post-capillary venules 2 SCD cellular and animal models: interruption of selectin-mediated cellular adhesion decreases erythrocyte and leukocyte adhesion to the endothelium and improves blood flow 3 7 L-selectin CD15c E-selectin Neutrophil entry into tissues CD11b CD11a P-selectin Attachment (rolling) Fibronectin Collagen Extracellular matrix Laminin IL-8 Adhesion Diapedesis 1. Tedder TF, et al. FASEB J. 1995;9: Ley K, et al. Nat Rev Immunol. 2007;7: Chang J, et al. Blood. 2010;116: Matsui NM, et al. Blood. 2001;98: Matsui NM, et al. Blood. 2002;100: Embury SH, et al. Blood. 2004;104: Kutlar A, et al. Am J Hematol. 2012;87:536-9.

83 Non-inferiority trial design; primary study endpoint: 24-month TCD velocity The transfusion arm maintained children at HbS <30%; an elevated liver iron concentration (LIC) identified by R2 MRI FerriScan was managed with chelation. The hydroxyurea arm included an overlap period with transfusions until a stable maximum tolerated dose (MTD) of hydroxyurea was reached; transfusions were then replaced by serial phlebotomy to reduce iron overload. In both arms, TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators masked to the results. A centralized TCD alert algorithm monitored changes from enrollment velocities. 159 children enrolled: 38 failed screening severe vasculopathy on MRA or inadequate TCD exams 121 children were randomized (61 to transfusions, 60 to hydroxyurea) Children randomized to transfusions maintained an average HbS <30% Hydroxyurea arm: MTD after 7 ± 2 months at an average dose of 27 mg/kg/day,hematological changes including HbF ~25% throughout the treatment period

84 The effect of hydroxyurea on compound heterozygotes for sickle cell-hemoglobin D-Punjab A single centre experience in eastern India Pediatric Blood & Cancer Volume 61, Issue 8, pages , 24 FEB 2014 DOI: /pbc

85 Low and fixed dose of hydroxyurea is effective and safe in patients with HbSβ+ thalassemia with IVS1-5(G C) mutation Pediatric Blood & Cancer Volume 62, Issue 6, pages , 24 DEC 2014 DOI: /pbc

86 Low and fixed dose of hydroxyurea is effective and safe in patients with HbSβ+ thalassemia with IVS1-5(G C) mutation Pediatric Blood & Cancer Volume 62, Issue 6, pages , 24 DEC 2014 DOI: /pbc

87 Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, noninferiority trial Figure 1. Trial profile*two participants were excluded for two reasons. null, Volume 387, Issue 10019, 2016,

88 Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, noninferiority trial Figure 2. Laboratory parameters of the intention-to-treat populationresults are shown for haemoglobinconcentration (A); mean corpuscular volume (B); sickle haemoglobin (C); fetal haemoglobin(d); white blood cell count (E); absolute neutrophil count (F); abso... null, Volume 387, Issue 10019, 2016,

89 Figure 3. Primary endpoint analysis of TCD velocitiestcd data are shown by use of mixed model statistical analysis (A); the curves are significantly different using the non-inferiority comparison (p= ) and also by post-hoc analysis for superiority (... Lancet, Volume 387, Issue 10019, 2016,

90 Hazard Ratio of Death for adults not on HU Rx compared to those on HU Rx for at least 17 years Study name Statistics for each study Rate ratio and 95% CI Rate Lower Upper ratio limit limit Z-Value p-value Voskaridou Steinberg Favours A Favours B Meta Analysis