SICKLE-CELL CELL DISEASE IN THE FIFTH DECADE

Transcription

1 SICKLE-CELL CELL DISEASE IN THE FIFTH DECADE James J. Stark, MD, FACP Medical Director, Cancer Program Maryview Medical Center Professor of Medicine Eastern Virginia Medical School

2 In 1960 Sir John Dacie described SCD as essentially a disease of childhood. * Estimated survival in 1973: 14.3 years 20% of deaths < 2 years old 13% years old 50% % after age 30 By 1994, 85% survival to age 20 *Dacie JV The haemolytic anaemias: congenital and acquired. New York: Grune & Stratton, 1960.

3 SCD in Adulthood Today Described recently as: ongoing complex management issues of a chronic illness of adulthood, characterized by an inexorable accrual of significant health problems that adversely affect the quality of life. Wierenga et al. Survival estimates for patients with homozygous sickle-cell cell disease in Jamaica: a clinic-based population study. Lancet 2001; 357:

4 Today s s Topics What happens to people who survive SCD into the fifth decade? What is new about the treatment of SCD, and what if anything can be done with these new approaches for this subset of patients?

5 Case : SM 48 y.o. A-A A A woman with severe SCD Spent childhood in Carrsville,, VA (Western Hampton Roads, small rural community) Describes sickly childhood with frequent painful episodes of the hands and feet; not diagnosed until moved to New Jersey and became pregnant Had very difficult pregnancy at age 21; hospitalized for three months after delivery; never attempted pregnancy again. Child has sickle trait. Case Case

6 SM, continued Hospitalized at age 24 for unilateral ureteral obstruction?? Renal papillary necrosis Frequent ICU admissions for Acute Chest Syndrome (ACS) gravely ill each time Frequent exacerbations associated with menses; had respite from illness after hysterectomy at age 35. On HRT (premarin( premarin) Has had laser treatments for proliferative retinopathy Tried on Hydroxyurea but could not afford to purchase it Case Case

7 SM, continued Over the last five years became increasingly ill with increasing frequency and duration of hospitalizations Hematocrit unsupported in high teens; gradually slipped into worsening congestive heart failure Several admissions characterized by acute renal failure responsive to hydration and transfusion Case Case

8 SM, continued In conjunction with SCD team from MCV we embarked on a treatment of prophylactic red-cell transfusions Has markedly reduced frequency of admissions Enabled her to slowly gain weight Improved exercise tolerance and general sense of well-being Serum ferritin 1500 pre-transfusion program, now 6500; attempting to initiate chelation program; finances an issue Has frequent severe transfusion reactions despite using leuko-poor product Case Case

9 SM, continued Other problems remained: Moderate hypertension (BP about 160/90) before change in medicine (see below) Creatinine clearance 47ml/min 24-hour urinary protein 1957 mg; started on Fosinopril (Monopril ) about a year ago as replacement for Amlodipine (Norvasc ) to try to reduce proteinuria; ; daily protein excretion now about 450; BP under better control Creatinine has fallen from 3.0 to 1.7 mg/dl Case Case

10 SM: quality of life, continued Married to man with relatively mild SC disease; remarkable synergy and understanding Despite improvement takes Dilaudid 2 mg up to 100 times per month; intolerant of long-acting opiates Pain is now more manageable whereas was in severe pain much of the time despite analgesics Case Case

11 Sickle-Cell Anemia Single base-pair substitution on chromosome 11 resulting in substitution of valine for glutamic acid at the 6 th position on the ß-chain of hemoglobin molecule Mutation results in hemoglobin polymerization and subsequent rigidity of cells Polymerization results in altered morphology of erythrocytes with irreversible sickling at low ph or p0 2 Case Case

12 The Normal ß-chain of Hemoglobin Case Case

13 Case Case

14 SCD: fundamentals, continued Severity of clinical illness variable; depends in part on other secondary inherited mutations in hemoglobin (varies with geography of Africa) Traditional mainstays of therapy during painful (vaso-occlusive) occlusive) crisis: Analgesics Hydration Supplemental oxygen Transfusions traditionally shunned because of the eventual problem of iron overload All of the above are being re-examined examined today Case Case

15 Nitric Oxide Depletion in SCD: concept in evolution Nitric Oxide critical to maintaining vasodilation under a variety of scenarios Pathologic hemolysis is a hallmark of SCD with dramatically shortened RBC survival Hemolysis from SCD or other conditions causing intravascular hemolysis (e.g., PNH) results in release of free hemoglobin into circulation Hgb remains in circulation until RES can eliminate it Bad things result from this. Case Case

16 Consequences of Hemolysis to Nitric Oxide Metabolism Key event NO converted to Nitrate (NO3) Downstream events

17 Damage from SCD Polymerization of hemoglobin leads to irreversible sickling and occlusion of small blood vessels leading to pain and tissue death Reduction in available Nitric Oxide reduces major mechanism to compensate for vaso- occlusion Leads to irreversible vaso-occlusion occlusion and potentially catastrophic tissue damage, e.g., stroke, myocardial infarction, pulmonary infarction Case Case

18 SCD in Adulthood Defining the problem: excess mortality Case Case

19 Survival with Sickle disease, continued Case Case

20 Sorting Out the Excess Mortality: The Cooperative Study of Sickle Cell Disease Funded by NHLBI Followed 3764 patients with SCD, Sickle C disease and Sickle-cell cell-ß-thalassemia 209 patients died during period of observation (10 years) Causes of death analyzed Case Case

21 Causes of death in 171 patients without known underlying organ failure in CSSCD Case Case

22 Deaths in patients with known organ failure 38 out of 209 deaths in CSSCD Case Case

23 Summary of risk factors for early death in adults with SCD (CSSCD) Case Case

24 Overview of Natural History of SCD in Adults Acute Chest Syndrome Chronic Pulmonary Complications Cardiac Disease Renal Disease Infectious Complications Ophthalmologic Disease Chronic Pain Psychosocial Burden Case Case Natural Natural History/Complications History/Complications

25 Acute Chest Syndrome Acute illness with: fever, respiratory symptoms, and new infiltrate on chest x-rayx Higher incidence in children but higher mortality in adults (4-9% per event). Best data from the National Acute Chest Syndrome Study Group Landmark study published: 671 episodes in 538 patients Case Case Natural Natural History/Complications History/Complications

26 Symptoms at Onset of Acute Chest Syndrome key findings (expressed as %) Case Case Natural Natural History/Complications History/Complications

27 Case Case Natural Natural History/Complications History/Complications

28 Case Case Natural Natural History/Complications History/Complications

29 Case Case Natural Natural History/Complications History/Complications

30 Causes of Acute Chest Syndrome Case Case Natural Natural History/Complications History/Complications

31 Pathogens Isolated in 570 Episodes of Acute Chest Syndrome Case Case Natural Natural History/Complications History/Complications

32 Treatment: ACS, continued Oxygen Transfusion to decrease % sickle cells Empiric antibiotics to include Mycoplasma coverage Incentive spirometry Bronchodilators if evidence of airway hyperreactivity??nitric Oxide Conventional wisdom about hydration during crisis may be counterproductive; may increase likelihood of pulmonary edema especially in older patients Severe complication of SCD, with higher mortality in adults Repeated episodes may lead to chronic respiratory insufficiency and shortened life expectancy Case Case Natural Natural History/Complications History/Complications

33 Chronic Pulmonary Complications May be related to frequency of ACS Pulmonary hypertension Treated with usual measures including nocturnal low-flow oxygen, calcium channel blockers Some enthusiasm for long-term anticoagulation Long-term red-cell transfusion therapy Case Case Natural Natural History/Complications History/Complications

34 Cardiac Complications of SCD Cardiomegaly Elevated cardiac output Hypertension, multifactorial,, including possible role of renal ischemia or focal infarction HBP very deleterious to life-style and outcome Should be treated aggressively especially when associated with proteinuria Autonomic dysfunction contributes to much higher than expected incidence of sudden death Congestive heart failure an ominous development (as with our patient SM) Role of transfusions Case Case Natural Natural History/Complications History/Complications

35 Transfusions in SCD Historically shunned: Iron overload with no convenient way to get rid of burden Alloimmunization with minor blood group antigens making cross- matching increasingly difficult Clearly shorten duration of crisis and can probably lower frequency of crises when given on regular basis Transient enthusiasm for chronic partial exchange transfusions waning in recent years Not usually done prophylactically except in special circumstances (our patient) Oral iron chelating agent in development Case Case Natural Natural History/Complications History/Complications

36 Renal abnormalities in SCD Renal medulla especially susceptible to injury from sickling (hypertonicity,, low ph, hypoxia) Significant loss of vasa recta Hyposthenuria leads to dehydration Renal tubular acidosis Defects in potassium excretion Case Case

37 Renal abnormalities, continued Hematuria may indicate renal papillary necrosis (as with our patient) Acute renal failure seen often during severe acute painful crisis Proteinuria predicts for development of end-stage renal disease May respond to ACE inhibitors Case Case

38 ACE Inhibitors in SCD with Proteinuria Short-term term clinical trials; no long-term data yet Among SCD patients age 40, 7-10% 7 have elevated serum creatinine 25% have at least mild proteinuria Earliest renal lesion is glomerular enlargement During enalapril administration urinary protein 57%; some benefit remained after drug was discontinued No change in blood pressure noted in this study; no deleterious effect on normotensive patients Case Case Falk et al NEJM 326:910-5, 1992

39 Renal Disease, continued Need long-term data on prevention of ESRD with ACE inhibitors At present best advice is strict BP control with use of ACE inhibitors as part of treatment of hypertension and consideration for any SCD patient with significant proteinuria Case Case

40 Infectious Complications Functional asplenia Opsonizing defect in WBC s Excess mortality in children from Strep. Pneumoniae not seen in adults Salmonella infections more common, including osteomyelitis Excess morbidity and mortality from influenza outbreaks, hepatitis B Parvovirus B19 can cause aplastic crisis Case Case Natural Natural History/Complications History/Complications

41 Ophthalmologic Complications Variety of retinal lesions Natural history depends on type of hemoglobinopathy and perhaps on degree of anemia Patients with SC tend to have more retinal problems Lesions are progressive; natural history can be interrupted Traumatic eye injuries (hyphema( hyphema) ) can cause massive intraocular sickling leading to IOP and central retinal artery occlusion When in doubt in ER setting screen for hemoglobinopathy Case Case Eye Eye Complications Complications

42 Stages of retinal changes in SCD Sickle Cell Stages Stage I Stage II Stage III Stage IV Stage V peripheral arteriolar occlusions peripheral arterio-venular anastomoses neovascularization vitreous hemorrhage retinal detachment Case Case Eye Eye Complications Complications

43 Retinal Lesions: peripheral arteriolar occlusions Case Case Eye Eye Complications Complications

44 Sea-fan neovascularization Case Case Eye Eye Complications Complications

45 Sea-fan neovascularization after laser treatment Case Case Eye Eye Complications Complications

46 Sea-fan neovascularization auto-infarcted Case Case Eye Eye Complications Complications

47 Several lesions together Neovascular frond or Sea Fan Choroidal infarct Pre-retinal hemorrhage Case Case Eye Eye Complications Complications

48 Pain Management Hallmark of acute pain is vaso-occlusive occlusive event Typically required several days of analgesics and often in-hospital care Use of meperidine (Demerol ) a problem; often use has to be proscribed by physician Problem of transient euphoria Problem of toxic metabolites; seizures common Problem of short half life Personal favorite is hydromorphone (Dilaudid ) either oral or parenteral; can be given by continuous infusion or PCA with success in acute painful crisis Case Case Management Management

49 Chronic Pain, continued Much bigger problem in the older sickle cell patient is chronic pain Most patients over 40 take some form of narcotic analgesic daily even if they seem outwardly well Pain thought to be from bone infarcts, compression fractures; high incidence of avascular necrosis Little scholarly work available to guide the clinician in management Long-acting narcotics (e.g., fentanyl patch, slow-release morphine products) very useful if patients will agree to take Use of NSAID s s advocated for narcotic-sparing effect, but prevalence of renal disease in older SCD population makes routine use problematic Case Case Management Management

50 Psychosocial Burden of Disease Inability to keep steady job Living in fear of painful crises Family dynamic as the invalid of the family Perception of pariah status among health-care providers Issues related to narcotic use/abuse Racial overtones between patient and health-care professionals No easy solution to above issues Hint: try to see patients outside of hospital setting; use office as staging area to work on disease management, crisis prevention Case Case Management Management

51 Contemporary Management of Sickle Cell Disease: The Hydroxyurea Story Case Case

52 HU and Fetal Hemoglobin Immediately after birth the body switches from making γ chains to ß chains resulting in loss of fetal hemoglobin Fetal hemoglobin is distributes heterogeneously within erythrocytes: About 1/3 of sickle RBC s can have some HbF Total percentage of HbF is, however, usually only about 5% Case Case

53 The Switch from γ to ß Synthesis of γ chains is repressed by methylation of DNA Hypomethylating agents can stimulate production of γ chains First agent tried was 6-azacytidine6 Hydroxyurea then tried safer, easier to use Initial pilot studies showed: HbF and MCV related to dose of HU MTD had to be determined case by case Magnitude of HbF increase related to initial HbF level Case Case

54 The Multicenter Study of HU (MSH) The Study: 299 adults with >3 crises/year randomized to HU or placebo Dose of HU started at 15 mg/kg; modified by toxicity; duration of trial planned at 2 years End points: Number of painful crises Death rate Development of Chest Syndrome Changes in Hb and HbF levels Differences between groups were so striking that the trial was ended prematurely. Case Case Multicenter Multicenter Hydroxyurea Hydroxyurea Study Study

55 Patients at entry to MSH Charache et al NEJM 332:1317, 1995 Case Case Multicenter Multicenter Hydroxyurea Hydroxyurea Study Study

56 Painful Crises: HU vs. placebo (rate/year) Case Case Multicenter Multicenter Hydroxyurea Hydroxyurea Study Study

57 % F Cells over time Case Case Multicenter Multicenter Hydroxyurea Hydroxyurea Study Study

58 Sentinel events during treatment Charache et al Medicine (Balt)75:300, 1996 Case Case Multicenter Multicenter Hydroxyurea Hydroxyurea Study Study

59 Current Recommendations for use of Hydroxyurea in SCD Hydroxyurea in all adults with SCD who experience more than 3 painful crises/yr sufficient to require hospitalization Requires high degree of compliance because of potential of myelosuppression To date no evidence of long-term side effects especially myelodysplasia or myeloid leukemia Most likely to be effective if initial HgF is > 5% Case Case Management Management

60 Cutting-Edge Strategies Gene therapy Stem-cell hematopoietic transplantation from HLA-identical donors Case Case Cutting Cutting Edge Edge

61 Gene Therapy for SCD Goal: introduce gene for normal globin synthesis into erythron of SCD patient HIV-based viruses most efficient transmitters of novel genetic material Mouse models show feasibility of approach Case Case Cutting Cutting Edge Edge

62 Murine experimental SCD Transgenic mice created which express Human ß-globin Custom designed ß-globin variant which would prevent HbS polymerization Introduced into mice via lentiviral vector Anti-sickling protein accumulated in 52% of total hemoglobin and 99% of red cells Case Case Cutting Cutting Edge Edge

63 Gene therapy, continued Rendering HIV (lentiviral( lentiviral) ) sequences harmless yet capable of propagation a huge challenge Amplification of new cell line in vivo remains additional challenge How much regular hemoglobin is required to ameliorate syndrome in humans is unknown Alternative approach is to introduce gene to upregulate fetal hemoglobin synthesis Case Case Cutting Cutting Edge Edge

64 Novel Strategies, continued: Bone-Marrow/Stem Marrow/Stem-Cell Transplantation HLA-identical donor can be found among siblings who are not homozygous SS Histocompatibility genes on different chromosomes from Globin genes Major experience thus far in children (mean age 8) 91% survival; 82% survive without clinical SCD 11% frequency of stable mixed chimerism 25% incidence of graft-versus versus-host disease 25% incidence of major neurologic complications (mostly new onset seizures) Case Case Cutting Cutting Edge Edge

65 Current Status of Transplant Morbidity and mortality from procedure remain quite high, as immunologic barriers are formidable Donor pool (unrelated donors) limited African Americans under-represented represented in International Bone- Marrow Registry Probably should be reserved for sickest patients; key is to proceed before end-organ damage precludes procedure; patients over 40 have probably waited too long Timing is difficult By achieving chimeric state one can prevent future crises without totally ablating marrow of recipient Case Case Cutting Cutting Edge Edge

66 Summary of Management Anticipate potential for end-organ damage: Blood-pressure control ACE inhibitors for proteinuria Regular ophthalmologic examinations Consider hydroxyurea for patients with high frequency of painful crises Consider regular transfusions for sickest patients Keep an open mind about potential cutting-edge technologies such as bone-marrow transplantation Recognize potential for catastrophic complications in hospitalized patients Create a nurturing milieu for patients needing chronic care Case Case Management Management

67 Acknowledgements Mrs. SM and her devoted family Dr. Wally Smith at MCV Dr. Richard Snyder, Dept. of Medicine, EVMS Drs. Peter Mitrev and Mark McCarthy for ophthalmologic advice School of Optometry at IU Medical Center Case Case Acknowledgements Acknowledgements

68 For more information and for a hard Visit.. copy of this talk.

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