Tags

Type your tag names separated by a space and hit enter

Spectrum of fetal hemoglobin responses in sickle cell patients treated with hydroxyurea: the National Institutes of Health experience.

Abstract

Hydroxyurea is one of several cytostatic agents that increase fetal hemoglobin (HbF) production in some patients with sickle-cell disease, although their mechanisms of action remain to be defined. We have studied the effects of hydroxyurea in several hospitalized patients with sickle-cell disease treated for 3 months, who were then maintained on outpatient therapy. Among hydroxyurea-treated patients, we found that about 75% respond with at least a twofold increase in the percentages of F reticulocytes and HbF. Among the responders, HbF levels increased twofold to 10-fold, with three patients achieving levels of 10% to 15%. Statistical analysis of the three cellular variables that determine HbF levels in patients with sickle-cell disease--namely, increased F-cell production, F-cell survival, and HbF/F cells--disclosed that HbF production, as measured by an increase in F reticulocytes, accounted for about 70% of the HbF elevation, with smaller contributions coming from augmentation of HbF/F cells and preferential survival of F cells. Four responders were re-treated with their optimal weekly hydroxyurea dose, given either in daily fractions or over 4 consecutive days, after a 1- to 3-month washout period. Greater HbF responses were attained with the optimal hydroxyurea dose than with the dose-regimen escalation, and usually occurred after a lag period. Furthermore, increases in HbF and F-cell levels were more rapid in patients receiving therapy on 4 out of 7 days rather than on a daily schedule. Our calculations show that the increases in HbF/F and F cells and the decrease in the fraction of dense cells during limited hydroxyurea administration should cause a significant improvement in intracellular sickle hemoglobin polymerization tendency. Controlled prospective trials are necessary to establish whether these effects lead to clinical benefit. Alternate schedules of hydroxyurea administration, or its use in conjunction with other means to elevate HbF or reduce mean cell hemoglobin concentration, may achieve greater inhibition of polymerization and thus be more likely to result in unequivocal amelioration of disease manifestations.

Links

Authors+Show Affiliations

Laboratory of Chemical Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.

Source

Seminars in oncology 19:3 Suppl 9 1992 Jun pg 67-73

MeSH

Anemia, Sickle Cell
Drug Administration Schedule
Erythropoiesis
Fetal Hemoglobin
Hemoglobin, Sickle
Humans
Hydroxyurea
National Institutes of Health (U.S.)
Reticulocytes
Time Factors
United States

Pub Type(s)

Journal Article

Language

eng

PubMed ID

1379375

Citation

Rodgers, G P.. "Spectrum of Fetal Hemoglobin Responses in Sickle Cell Patients Treated With Hydroxyurea: the National Institutes of Health Experience." Seminars in Oncology, vol. 19, no. 3 Suppl 9, 1992, pp. 67-73.
Rodgers GP. Spectrum of fetal hemoglobin responses in sickle cell patients treated with hydroxyurea: the National Institutes of Health experience. Semin Oncol. 1992;19(3 Suppl 9):67-73.
Rodgers, G. P. (1992). Spectrum of fetal hemoglobin responses in sickle cell patients treated with hydroxyurea: the National Institutes of Health experience. Seminars in Oncology, 19(3 Suppl 9), pp. 67-73.
Rodgers GP. Spectrum of Fetal Hemoglobin Responses in Sickle Cell Patients Treated With Hydroxyurea: the National Institutes of Health Experience. Semin Oncol. 1992;19(3 Suppl 9):67-73. PubMed PMID: 1379375.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Spectrum of fetal hemoglobin responses in sickle cell patients treated with hydroxyurea: the National Institutes of Health experience. A1 - Rodgers,G P, PY - 1992/6/1/pubmed PY - 1992/6/1/medline PY - 1992/6/1/entrez SP - 67 EP - 73 JF - Seminars in oncology JO - Semin. Oncol. VL - 19 IS - 3 Suppl 9 N2 - Hydroxyurea is one of several cytostatic agents that increase fetal hemoglobin (HbF) production in some patients with sickle-cell disease, although their mechanisms of action remain to be defined. We have studied the effects of hydroxyurea in several hospitalized patients with sickle-cell disease treated for 3 months, who were then maintained on outpatient therapy. Among hydroxyurea-treated patients, we found that about 75% respond with at least a twofold increase in the percentages of F reticulocytes and HbF. Among the responders, HbF levels increased twofold to 10-fold, with three patients achieving levels of 10% to 15%. Statistical analysis of the three cellular variables that determine HbF levels in patients with sickle-cell disease--namely, increased F-cell production, F-cell survival, and HbF/F cells--disclosed that HbF production, as measured by an increase in F reticulocytes, accounted for about 70% of the HbF elevation, with smaller contributions coming from augmentation of HbF/F cells and preferential survival of F cells. Four responders were re-treated with their optimal weekly hydroxyurea dose, given either in daily fractions or over 4 consecutive days, after a 1- to 3-month washout period. Greater HbF responses were attained with the optimal hydroxyurea dose than with the dose-regimen escalation, and usually occurred after a lag period. Furthermore, increases in HbF and F-cell levels were more rapid in patients receiving therapy on 4 out of 7 days rather than on a daily schedule. Our calculations show that the increases in HbF/F and F cells and the decrease in the fraction of dense cells during limited hydroxyurea administration should cause a significant improvement in intracellular sickle hemoglobin polymerization tendency. Controlled prospective trials are necessary to establish whether these effects lead to clinical benefit. Alternate schedules of hydroxyurea administration, or its use in conjunction with other means to elevate HbF or reduce mean cell hemoglobin concentration, may achieve greater inhibition of polymerization and thus be more likely to result in unequivocal amelioration of disease manifestations. SN - 0093-7754 UR - https://www.unboundmedicine.com/medline/citation/1379375/Spectrum_of_fetal_hemoglobin_responses_in_sickle_cell_patients_treated_with_hydroxyurea:_the_National_Institutes_of_Health_experience_ DB - PRIME DP - Unbound Medicine ER -