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Efficacy of Hydroxyurea in Providing Transfusion Saqib H. Ansari, MBBS, DCH, DPGN, MPhil, Tahir S. Shamsi, MBBS, FRCPath, Mushtaq Ashraf, MBBS, MD, Kousar Perveen, BSc, MBA, CRA, Tasneem Farzana, MBBS, MCPS, Munira Borhany, MBBS, FCPS, Sajida Erum, Pharm D, CCRP, and Tabassum Mehboob, PhD in the general population with an increased risk of Background: Packed red blood cell (PRC) transfusion with iron transfusion-transmitted infections. Therefore, efforts are chelation is the mainstay of treatment for b-thalassemia major. being made to implement preventive strategies, but simulta- This prospective interventional trial serves as a follow up to our neously researchers are also looking for nontransfusion similar earlier study that evaluated the efficacy and safety of hydroxyurea (HU) in minimizing PRC transfusions in patients with Beta-thalassemia is characterized by insufficient produc- tion of adult b-globin chains with subsequent accumulation Methods: One hundred fifty-two patients with b-thalassemia major of aggregates of unpaired insoluble a-globin chains, which received HU at a mean dose of 16 mg/kg/d. The results were leads to hemolytic anemia, ineffective erythropoiesis, and analyzed at the end of 24 months. Transfusion requirement during intramedullary destruction of erythroid cells. However, the 6 months preceding the study was considered as the control. affected infants maintain normal Hb levels till the first couple Results: One hundred forty-six of 152 patients were evaluated after of months after birth due to fetal hemoglobin (HbF), which 24 months of follow up; 6 patients were either lost to follow-up or has a and g-globin chain combination; but methylation of withdrew consent. Grade 1 myelosuppression was observed in 4 g-globin gene at this time switches off HbF synthesis. patients and diarrhea in 2 patients. Sixty children (41%) did not Therefore, reactivation of fetal g-globin gene expression is require any transfusion after using HU; 57 patients (39%) showed an appealing therapeutic approach to the management of partial response with greater than 50% reduction in PRC b-thalassemia, as the fetal g-globin genes are universally transfusion; and 29 patients (20%) were nonresponders with less present and thereby can lead to correction in the imbalance than 50% reduction in PRC transfusion. The mean volume of PRC transfused was reduced for all patients. of a/non-a-globin chains found in b-thalassemia. Various therapeutic agents, for example, erythropoietin, 5-azacytidine, Conclusions: HU was found to be safe in patients with b- butyrate derivatives, and hydroxyurea (HU), have been thalassemia major, and resulted in the reduction of transfusion investigated for their therapeutic potential of HbF augmenta- requirement and in an increase in the interval between transfusions. Key Words: hydroxyurea, b-thalassemia major, transfusion volume HU, a potent ribonucleotide reductase inhibitor, is a well-known chemotherapeutic agent that has been used for (J Pediatr Hematol Oncol 2011;33:339–343) the treatment of various myeloproliferative conditions. HU rapidly clears a large number of normally dividing pre- cursors, resulting in acute erythropoietic stress that recruits T halassemias are a heterogeneous group of inherited early erythroid precursors from the G phase of cell cycle, disorders of hemoglobin (Hb) synthesis resulting in life- resulting in g-chain synthesis in the erythroid progeny. threatening anemia and require regular blood transfusion However, it has been postulated that the presence of G-158 for survival.1 The World Health Organization has identified C>T polymorphism (Xmn1) is associated with better control of hemoglobinopathies, particularly b-thalassemia, g-globin gene reactivation.7,8 The potential of HU to induce in developing world as a priority.2 Estimated 5000 to 9000 HbF synthesis, both in anemic monkeys and in patients children with b-thalassemia are born annually and the with sickle cell disease, has been reported.9–11 Clinical and projected carrier rate is 5% to 7%, with 9.8 million carriers hematologic benefits have been reported in patients with in the total population.3 In Pakistan, the average annual thalassemia intermedia treated with HU.12,13 The response expense of management of a child with thalassemia is US of HU in thalassemia major has been studied in small series $4400 per patient, this is 10 times the annual per capita of patients14–18; indeed, Bradai et al15 have reported a income.4 In addition, sufficient safe blood is not readily sustained level of Hb after treatment with HU, which available and there is a high prevalence of hepatitis B and C resulted in discontinuation of transfusion in all 7 patients treated. Dixit et al19 have mentioned an association with a3.7 deletions in the heterozygous state, which was seen as a Received for publication October 4, 2010; accepted February 28, 2011. predictor of good response to HU therapy; however, all From the Department of Pediatric Hematology, National Institute of cases with this mutation also had the presence of Xmn1 Reprints: Saqib H. Ansari, MBBS, DCH, DPGN, MPhil, Department polymorphism, suggesting a combination of variables of Paediatric Haematology, National Institute of Blood Diseases, affecting the final response. Earlier, we reported the clinical ST 2/A, Block 17, Gulshan-e-Iqbal, KDA Scheme 24, Karachi, and hematologic improvements from the use of HU in our Pakistan (e-mail: [email protected]). Copyright r 2011 by Lippincott Williams & Wilkins patients with thalassemia major; the mean volume of J Pediatr Hematol Oncol • Volume 33, Number 5, July 2011 J Pediatr Hematol Oncol • Volume 33, Number 5, July 2011 packed red blood cell (PRC) transfused was reduced in all defined by a fall in the leukocyte counts to less than 1500/ study subjects from 2126.45 to 1489.59 mL (P<0.05).17 mL, platelet counts to less than 80,000/mL, Hb of 6 g/dL, a The interval between transfusion was increased by 68.7%. 2-fold rise in alanine aminotransferase or aspartate amino- Grade 1 myelosuppression was observed in 4 patients and transferase, and as a greater than 50% increase in serum diarrhea in 2 patients. This study is an update on the safety and efficacy of HU, in a larger number of patients with Outcome variable was PRC transfusion required during the 24 months on HU. Initially, patients were reviewed every week for 1 month and then every 15 days for 24 months. On every visit, thorough clinical examination was conducted and blood counts were measured. At 6th, One hundred fifty-two children attending the out- 12th, and 24th month, serum ferritin, echocardiography, patient department at National Institute of Blood Diseases and abdominal ultrasound were repeated. Criteria for were inducted in the trial. This study was conducted from transfusing a patient after initiating the intervention were July 2003 to June 2008 according to the Declaration of both, Hb of 6 g/dL and symptoms or signs of anemia (that Helsinki. Institutional ethical committee approved this trial is, lethargy, dyspnea, tachycardia, edema, and loss of and written informed consent in the local language was appetite), or infection (even if the Hb >6 g/dL). HU was obtained from the patients or their parents. withheld if there were side effects such as marrow suppres- sion, gastrointestinal symptoms, or elevation of creatinine levels above 2 times the normal range. Response criteria The inclusion criteria are (A) age above 1 year, (B) having been registered at our center for at least last 6 months, (C) diagnosis of b-thalassemia major (defined as Hb <7 g/dL, high HbF, absent or very low HbA, and more than 8 transfusions a year; diagnosis was confirmed by These are children who were on regular transfusion or DNA analysis where required), and (D) b-thalassemia a candidate for PRC transfusion but remained transfusion intermedia characterized by hemolytic anemia, but with independent (maintaining Hb >7 g/dL) on HU. They were maintenance of Hb between 7 and 10 g/dL without trans- subclassified as: (a) group A responders—children on fusion, at least until the age of 2 years. Patients having any regular blood transfusion before starting HU and became evidence of other chronic illnesses unrelated to thalassemia completely transfusion independent after starting HU; and and hypersensitivity to HU were excluded. Criteria for (b) group B responders—children who were never trans- noncompliance were lack of follow up in the clinic before fused (although their Hb dropped to less than 6 g/dL or one-third of the study was completed or failure to keep they showed signs of extramedullary hematopoeisis such as 50% of appointments in the first 12 months of study. hepatosplenomegaly and facial changes) and showed a Furthermore, at every follow-up, the remaining capsules of significant rise in Hb without transfusion; practically, this HU were counted to evaluate therapeutic compliance. group comprised of b-thalassemia intermedia cases. Historic controls were used in this trial, that is, history and record of blood transfusion of the same patients observed for 6 months preceding the intervention served as control. A detailed medical history and physical examination These are children who were on regular PRC transfu- were obtained upon entry into the study. Before commen- sion before HU, remained on PRC transfusion but showed cing HU, all patients underwent baseline laboratory testing more then 50% reduction in transfusion in comparison that included a complete blood count, liver function, renal with the control period, that is, 24 months before starting function, serum ferritin, anti-human immunodeficiency virus antibodies, anti-hepatitis C virus antibodies, hepatitis B surface antigen, DNA analysis for b-thalassemia muta- tions, Hb electrophoresis (for HbF), ultrasound abdomen, These are children who were on regular PRC transfu- and echocardiography. Biochemistry was performed using sion before HU and showed only minimum response, that Merck kits (Germany) and complete blood count was is, less then 50% reduction in transfusion requirement carried out using a Sysmex SF 3000 analyzer (Sysmex Corp, during the study period in comparison with the control KOBE, Japan). Viral markers were performed using Ortho- Clinical Diagnosis (Vitros ECiQ Immunodiagnosis System, Rochester). Hb electrophoresis was carried out using a Helena Biosciences electrophoresis system (Helena Labora- tories, TX). Echocardiography and abdominal ultrasound Means and SD were reported where data were were carried out using a Logic book X.P (G.E. Medical distributed normally; otherwise, median and ranges were reported. The paired t test was used for estimating the Mutation analysis was performed in 93 cases by significant difference between the preintervention and polymerase chain reaction, on the basis of the allele-specific postintervention values. Treatment observation period priming known as Amplification Refractory Mutation Sys- was 4 times that of the preintervention period, and thus tem, for the common b-thalassemia genes prevalent in the the total volume of PRC transfused during treatment was country. The children were prescribed HU (Cap. Hydrea, divided by 4. We also analyzed any statistically significant Bristol-Myers Squibb, Italy) at a mean dose of 16 mg/kg/d; reduction in frequency of PRC transfusion, as measured by the starting dose was 10 mg/kg/d and increased by 1 mg/kg average interval between 2 transfusions before and after the increments at 4-weekly intervals to a maximum of 20 mg/ treatment, and serum ferritin levels by using the paired kg/d or until myelotoxicity appeared. Myelotoxicity is r 2011 Lippincott Williams & Wilkins J Pediatr Hematol Oncol • Volume 33, Number 5, July 2011 HU in Providing Transfusion Independence in Thalassaemia One hundred forty-six patients were studied out of 152 on HU. Three patients were dropped because of noncom- pliance, 2 underwent splenectomy, and 1 child, who had cardiac complications from hemochromatosis, expired after 15 months of HU (already reported in the earlier article).17 The median age of the patients was 7.27 years (range: 1 to 23 y) with 72 of the subjects being female patients and 74 male patients. The mean age at first transfusion was 1.93 years (range: 3 mo to 5 y) and the mean Hb before starting therapy was 7.57 g/dL. The response to HU therapy was seen at a median of 65 days (range: 30 to 180 d) after starting the medicine. Sixty (41%) patients (responders) showed a sustained Hb level (Hb 7.6±1.5 and 7.8±1.5 g/dL) without any blood transfusion. Fifty-seven (39%) patients showed a partial response, whereas 29 (20%) patients were nonresponders. The mean volume of PRC Sixty children (41.09%) were in this group; 33 belonged to group A (18 male and 15 female patients), whereas the remaining 27 children were group B, with b- thalassemia intermedia (12 male and 15 female patients). The mean height and weight increased for both groups A and B as shown in Table 1. For group A, mean volume of PRC transfused in the control period before starting HU was 965.6 mL and during 24 months on HU they did not receive any PRC. After starting HU, mean Hb was maintained at 7.6 g/dL, although statistically this is not noteworthy as the children were on regular blood transfu- sion and the mean Hb during the control period was 7.5 g/dL. Group B (b-thalassemia intermedia) children had a baseline Hb of 6.7 g/dL that increased up to 7.8 g/dL. A decrease in serum ferritin was observed in both groups of responders. Hepatic and renal functions before and after intervention were unchanged as was the size of liver and spleen. For group A, Hb electrophoresis at baseline was not significant because of regular blood transfusion (as most Hb was from transfused blood); however, electrophoresis after HU showed high level of HbF. Group B showed a significant rise in Hb concentration along with a trend of a Fifty-seven patients (39.04%), 27 female and 30 male patients, experienced a reduction in volume of PRC transfused after HU intervention by 772 mL (P<0.05); this translates into a greater than 60% reduction. There was a significant increase in weight from mean weight of 14.8 to 18 kg; an increase in mean height from 96.25 to 101 cm; and a statistically insignificant decrease were observed in serum ferritin levels with a mean difference of 59.16 ng/L. Twenty- nine children (19.86%) showed only a reduction of 34% in PRC transfusion requirement, and as per the criteria for response were labeled as nonresponders. A statistically significant increase in mean weight and height was noted. Furthermore, the serum ferritin levels increased slightly. Desferoxamine was used as an iron chelation therapy by the children in study, but most of the children were not compliant to iron chelation therapy because of high cost and lack of resources. In partial responders and non- responders, HbF estimation was not of significance as they were still transfusion dependent. Transfusion interval was r 2011 Lippincott Williams & Wilkins J Pediatr Hematol Oncol • Volume 33, Number 5, July 2011 increased in partial responders from 39.64 (SD) days before is easy to use and well tolerated; toxicity is not significant even at a dose of 20 mg/kg, and in the rare instance HU can Eighteen (11%) patients were hepatitis C antibody cause transient leukopenia or thrombocytopenia. Tempor- positive, whereas only 2 were hepatitis B surface antigen ary discontinuation of the drug allows rapid normalization positive. None of the patients were human immunodefi- of the white blood cell count and the resumption of ciency virus positive. Mutation analysis for the common b- therapy. The response to HU therapy was evident at 65 thalassemia genes prevalent in the country was performed days (30 to 180 d) after starting HU and 41% of the in 93 cases, and as shown in Table 2, IVS 1-5 was the most patients, the responders, showed a sustained discontin- common mutation, irrespective of homozygosity/hetero- uation of transfusions. Even the partial responders and zygosity or the patient groups. The other mutations were nonresponders showed a reduction in PRC requirement by IVS 1-1, codon 30 (Cd 30), frameshift 8 to 9 (Fr 8 to 9), 50% and 34%, respectively; this spacing between transfu- frameshift 41-42 (Fr 41 to 42), codon 5 (Cd 5), codon 16 sions will help in reducing the pressure on demand for (Cd 16), and 619 bp deletion. IVS1-1, Cap+1, and E-b blood and its products, especially in the rural areas of thalassemia were associated with better response to HU. Pakistan (which constitute 60% to 70%), which have However, the number of children was not enough in each an absolute lack of blood banking services. A decrease group and hence the influence of genotype on response to was observed in serum ferritin levels in both responder groups, which could be because of the following reasons: Four children (2.7%) developed mild myelosuppres- (a) suppression of extramedullary erythropoiesis by HU; sion, which reversed within a week of withdrawal of HU. (b) complete cessation of blood transfusion requirement, Two patients (1.4%) developed diarrhea; HU was with- (c) better level of Hb concentration, which is associated drawn for 1 week, which relieved their symptoms. HU was with decreased absorption of iron from the intestine, and restarted in all these 6 patients subsequently and all of them (d) other yet unknown mechanism. There was no significant tolerated the medicine well afterward. Other side effects increase in spleen size in any group; thus, the increment in such as confusion, headache, hallucinations, rashes, prur- Hb was not at the cost of extramedullary hematopoietic itus, alopecia, dysuria, oliguria, or polyuria were not tissue enlargement in spleen, liver, or maxillary and observed in any of the patients and liver function, renal mandible bones. The resulting cessation of facial changes function, and blood counts remained comparable with the accompanied by improved exercise tolerance, increased baseline levels throughout the study. Most of the patients appetite and weight gain, better school attendance, and reported improved exercise tolerance and a sense of well improved socialization brought a healthy psychosocial effect on the children as noted in other studies.14,15,20 We identified an association between gene mutations, IVSI-I, Cap+1, and E-b thalassemia and a better response to HU. A total of 99.6% and 99.9% were the HbF Of the many pharmacologic agents that have been component in Hb electrophoresis of responder group A and used in the reactivation of HbF, HU has largely been the B, respectively, after HU therapy. Mean HbF% rise on HU drug of choice among patients with different hemoglobi- therapy was found more so in the group A of responders nopathies; the clinical benefit of this drug in sickle cell than in the group B (ie, the patients with thalassemia anemia has already been shown20 and experience with HU intermedia), but it must be understood that in both groups in b-thalassemia has met with variable success, albeit with of the responders, greater than 90% of Hb was HbF and much better results for b-thalassemia intermedia than therefore any increase in the Hb concentration represents major, the latter being inadequately evaluated.11–14,16,17 an increase in HbF concentration. Similar observation has Most of the studies included small numbers of patients, and been reported by Dixit et al19 who have suggested that this is the first study reporting the efficacy of HU in 119 possibly there are other mechanisms of action for HU as patients with b-thalassemia major and 27 with intermedia. In our study, all 146 patients showed clinical and The patient, who expired, was a splenectomized hematologic improvement after starting the medicine. HU 18-year-old man, who had organomegaly and high serum TABLE 2. Frequency of Gene Mutations Found in Patients With b-Thalassemia Cd indicates codon; Fr, frameshift; Hb, hemoglobin. r 2011 Lippincott Williams & Wilkins J Pediatr Hematol Oncol • Volume 33, Number 5, July 2011 HU in Providing Transfusion Independence in Thalassaemia ferritin before enrollment in the study and throughout the 9. Letvin NLDC, Linch P, Bearssky KW, et al. Augmentation of study. He was admitted for refractory cardiac arrhythmias fetal hemoglobin production in anemic monkeys by hydro- due to secondary hemochromatosis, and was unresponsive xyurea. N Engl J Med. 1984;310:317–323. to aggressive iron chelation therapy given for a month. 10. Miller BA, Platt O, Hope S, et al. Influence of hydroxyurea on fetal hemoglobin production in vitro. Blood. 1987;70: Therefore, probably this death is not associated with HU 11. Fibach E, Burke LP, Schechter AN, et al. Hydroxyurea HU is a promising drug in the treatment of patients increases fetal hemoglobin in cultured erythroid cells derived with b-thalassemia intermedia and b-thalassemia major from normal individuals and patients with sickle cell anemia. because it can safely, yet effectively, counter extramedullary hematopoiesis and increase the Hb level also. However, 12. Zeng YT, Huang SZ, Ren ZR, et al. Hydroxyurea therapy in careful and regular monitoring is required because of its b-thalassemia intermedia: improvement in hematological potential to cause cytopenia. Therefore, it should be admi- parameters due to enhanced b-globin synthesis. Br J Haematol. nistered only to those patients in who can maintain follow- 13. Olivieri NF. Reactivation of fetal hemoglobin in patients with b-thalassemia. Semin Hematol. 1996;33:24–42. 14. Arruda VR, Lima CSP, Saad STO, et al. Successful use of hydroxyurea in b-thalassemia major. N Engl J Med. 1997; 15. Bradai M, Abad MT, Pissard S, et al. Hydroxyurea can 1. Weatherall DJ, Clegg JB. The Thalassemia Syndromes. 4th ed. eliminate transfusion requirements in children with severe Oxford: Blackwell Science; 2001:288–289. b-thalassemia. Blood. 2003;104:114–117. 2. Angastiniotis M, Modell B. Global epidemiology of hemoglo- 16. Yavarian M, Karimi M, Bakker E, et al. Response to bin disorders. Ann NY Acad Sci. 1998;850:251–269. hydroxyurea treatment in Iranian transfusion-dependent 3. Ahmed S, Saleem M, Modell B, et al. Screening extended b-thalassemia patients. Haematologica. 2004;89:1172–1178. families for genetic hemoglobin disorders in Pakistan. N Engl J 17. Ansari SH, Shamsi TH, Siddiqui FJ, et al. Efficacy of hydroxyurea in reduction of pack red cell transfusion require- 4. Annual report of health services in Pakistan. Rawalpindi: ment among children having b-thalassemia major: Karachi HU Ministry of Health. Government of Pakistan. 1997. Trial. J Pediatr Hematol Oncol. 2007;29:743–746. 5. Perrine SP. Fetal globin induction—can it cure b-thalassemia? 18. Bianchi N, Zuccato C, Lampronti I, et al. Fetal hemoglobin Hematology Am Soc Hematol Educ Program. 2005;38–44. inducers from the natural world: a novel approach for 6. Rodgers GP, Sauntharajah Y. Advances in experimental identification of drugs for the treatment of b-thalassemia and treatment of b-thalassemia. Expert Opin Invest Drugs. 2001; sickle-cell anemia. Evid Based Complement Alternat Med. 7. Fucharoen S, Siritanaratkul N, Winichagoon P, et al. 19. Dixit A, Chatterjee TC, Mishra P et al. Hydroxyurea in Hydroxyurea increases hemoglobin F levels and improves the thalassemia intermedia—a promising therapy. Ann Hematol. effectiveness of erythropoiesis in b-thalassemia/hemoglobin 20. Charache S, Terrin MI, Moore RD, et al. Effect of 8. Italia KY, Jijina FJ, Merchant R et al. Response to hydroxyurea on frequency of painful crisis in sickle cell hydroxyurea in b thalassemia major and intermedia: experience anemia. Investigators of the Multicenter Study of Hydroxyurea in western India. Clin Chim Acta. 2009;407:10–15. in Sickle Cell Anemia. N Engl J Med. 1995;332:1317–1322. r 2011 Lippincott Williams & Wilkins

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