Desensitization to hydroxycarbamide following long-term treatment of thalassaemia intermedia as observed in vivo and in primary erythroid cultures from treated patients.
Hydroxycarbamide (HC) is a pharmacological agent capable of stimulating fetal haemoglobin (HbF) production during adult life. High levels of HbF may ameliorate the clinical course of β-thalassaemia and sickle cell disease. The efficacy of HC for the treatment of thalassaemia major and thalassaemia intermedia is variable. Although an increase of HbF has been observed in most patients, only some patients experience significant improvement in total haemoglobin levels. This study aimed to determine the effectiveness and safety of short- (1 year) and long-term (mean follow-up 68 months) HC treatment in 24 thalassaemia intermedia patients. Additionally, we evaluated if primary erythroid progenitor cells cultured from treated patients responded to HC treatment in a manner similar to that observed in vivo. Our results confirm a good response to HC after a short-term follow-up in 70% of thalassaemia intermedia patients and a reduction of clinical response in patients with a long follow-up. Erythroid cultures obtained from patients during treatment reproduced the observed in vivo response. Interestingly, haematopoietic stem cells from long-term treated patients showed reduced ability to develop into primary erythroid cultures some months before the reduction of the 'in vivo' response. The mechanism of this loss of response to HC remains to be determined.
Rigano
Paolo
P
U.O.C. Ematologia II, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
Pecoraro
Alice
A
Calzolari
Roberta
R
Troia
Antonio
A
Acuto
Santina
S
Renda
Disma
D
Pantalone
Gaetano Restivo
GR
Maggio
Aurelio
A
Di Marzo
Rosalba
R
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D015672:Erythroid Precursor Cells / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D005319:Fetal Hemoglobin / Q000096:biosynthesis; D005500:Follow-Up Studies; D005838:Genotype; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult; D017086:beta-Thalassemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics
D006454:Hemoglobins; D005319:Fetal Hemoglobin; D006918:Hydroxyurea