Is there a rationale for treatment of sickle cell anemia, NO, but JL Vives Corrons Red Cell Pathology Unit Hospital Clnic. University of Barcelona Head of ENERCA Project
EUROPEAN NETWORK FOR RARE AND CONGENITAL ANAEMIAS EUROPEAN CENTRES FOR HAEMOGLOBINOPATHIES UK FRANCE BELGIUM GERMANY ITALY SPAIN PORTUGAL GREECE Catalan Network for Major Haemoglobinopathies
EUROPEAN NETWORK FOR RARE AND CONGENITAL ANAEMIAS
ENERCA RECOMMENDATIONS FOR SICKLE CELL DISEASE American Journal of Haematology, 2010 In preparation, 2012
The modern management of sickle cell disease (SCD) is based on three therapeutic approaches: 1. Blood transfusion 2. Penicillin 3. Hydroxyurea (HU)
PRINCIPLE 1 HU has specific indications in SCD, but Not everyone with SCD should take HU as preventive therapy
The use of HU is indicated in SCD patients with one or more of the following problems Frequent painful episodes History of acute chest syndrome (ACS) History of other severe vasoocclusive crisis (VOC) Severe symptomatic anemia Very young children Griffin P. Rodgers (2012) Specific therapies for sickle-cell disease
PRINCIPLE 2 We should make every effort to treat children and adolescents with SCA before they develop chronic, inexorable, and ultimately fatal organ damage. HU appears to be the best available treatment option in symptomatic patients
Physiological beneficial effects of HU HbF Induction Reduce Haemolysis Improve Rheology Improve Rheology
Clinical beneficial effects of HU 1. Reduces frequency of VOC ad ACS 2. Reduces haemolysis and anaemia 3. Improves organ damage in adults (*) 4. Prevents cerebrovascular disease(**) (*) Acute Chest Syndrome (ACS) (**) Stroke
Evidence of effectiveness of HU treatment (*) Russell E. Ware. Blood 2010 115: 5300-5311 (3 year )
PRINCIPLE 3 Indication of long term HU administration (up to 8 years) should follow the principle of personalized treatment designed for each patient according to the clinical severity and the molecular phenotype
For personalized treatment one must consider: A First line treatment B Second line treatment D Prevention B. Gulbis, Belgium Protocol for the treatment of SCD
FIRST LINE TREATMENT WITH HU Consensus criteria for initiating treatment with HU in patients (> 24 months) with HbSS or HbS/β 0 thal (*) 1. Frequent Pain crises,including dactylitis 2. Acute Chest Syndrome (ACS) and vasoclussive crisis (VOC) 3. Severe chonic anaemia (hypoxemia) 4. Elevated Trans cranial doppler (TCD) velocity and its indication of cronic transfusion 5. Low hemoglobin F (HbF) 6. High WBC and Lactic dehydrogenase (*) Russell E. Ware. Blood 2010 115: 5300-5311
FIRST LINE TREATMENT WITH HU 1. Children (>2 Years) & Adults (Severe pain & anaemia, VOC, ACS) Treatment with HU (initial dose 15mg/Kg/day) 2. Very young children (< 2 years) (all clinical situations) Treatment with HU (initial dose: 20mg/Kg/day) 3. Children & adults with minimal disease activity No treatment G.P. Rodgers.Specific Theapies for SCD,2012
However, Some haematologists feel uncomfortable managing SCD adult patients with HU because: 1. Does not decrease the number of hospitalizations for VOC and ACS 2. Does not reduce transfusion requirements 3. It is cytotoxic 4. It creates uncertainties (effect on spermatogenesis and oncogenesis) Therefore efectiveness of HU in clinical practice has not always been realized.
UNCERTAINTIES OF LONG TERM HU TREATMENT Myelosupression (resolve by decreasing dosage or temporally interruption of administration). Decreased reticulocytes and Hb, PMN and platelets count. Incidence on men fertility ( inform the patient, sperm freezing) In case of pregnancy occurrence, stop HU treatment immediarely) Decreased of reticulocytes, Hb, neutrophil and PLT count Occurrence or recurrence of leg ulcer ( skin protection, avoid trauma or cold creams) Melanonychia, dry skin (inform the patient)
Barriers to Hydroxyurea Treatment (*) 1. Patients 2. Parents/family 3. Health providers 4. System (*) US.National Institute of Health. Consensus Conference (2007)
No clear consensus for Hydrea treatment (require a case by case decission) 1. Conditional Trans cranial doppler (TCD) velocities 2. Abnormal brain MRI (eg, silent infarcts) 3. Neurocognitive or neurosensorial decline 4. Age < 24 months 5. Poor growth and development 6. Parental request 7. High HbF 8. SCD genotype (*) Russell E. Ware. Blood 2010 115: 5300 5311
PRINCIPLE 4 HU should no be given to patients with high HbF, except in cases with severe complications
IMPORTANCE OF SCD genotype No indication for HU treatment in children Some indications in adults with stroke or severe neurosensorial involvement
CLINICAL SEVERITY OF SCD GENOTYPES
CLINICAL SEVERITY AND SCD GENOTYPES NEWBORN SCREENING IS AN IMPORTANT TOOL FOR PREDINCTING INDIVIDUAL COMPLEX SCD PHENOTYPES AND DESIGN A PERSONALIZED RATIONALE FOR TREATMENT IN CHILDREN
PRINCIPLE 5 Long term side effects of Hydrea administration such as increased risk of malignancy and reduced fertility, should be cause of concern when prescribing the drug for young children, who may take it for decades.
THANK YOU! I am grateful to : Dora Bachir (France) Beatrice Gulbis (Belgium) Lucia di Franceschi (Italy) Pere Gascon (Spain) Red Cell Pathology Unit Hospital Clinic i Provincial University of Barcelona c/ Villarroel 170 080036 Barcelona Phone: +34 934515950 enerca@enerca.org