Ann Hematol (2005) 84: 441–446DOI 10.1007/s00277-005-1026-4

ORIGINAL ARTICLE

Ashish Dixit . T. C. Chatterjee . Pravas Mishra .Dharma R. Choudhry . M. Mahapatra . S. Tyagi .Madhulika Kabra . Renu Saxena . V. P. Choudhry

Hydroxyurea in thalassemia intermedia—a promising therapy

Received: 15 August 2004 / Accepted: 13 February 2005 / Published online: 19 April 2005# Springer-Verlag 2005

Abstract Pharmacological agents such as hydroxyurea(HU) have been known to cause induction of fetal hemo-globin and possibly may alleviate the symptoms in thal-assemia intermedia patients. Thirty-seven patients withβ-thalassemia intermedia were enrolled to assess responseto HU therapy. Major response was defined as transfusionindependence or hemoglobin rise of more than 20 g/l andminor response as rise in hemoglobin of 10–20 g/l or re-duction in transfusion frequency by 50%. The median agewas 10 years (range: 4–50 years) and median follow-up was12 months (range: 4–36 months). Twenty-six patients(70.2%) showed response to HU therapy. Seventeen pa-tients (45.9%) were major responders, and nine patients(24.3%) showed minor response. There was no correlationof response with β-thalassemia mutation or XmnI polymor-phism; however, the presence of α3.7 deletion was asso-ciated with major response in three patients. Mean fetalhemoglobin (HbF) levels rose on HU therapy. Older age,low baseline F cell percent, and low baseline HbF levels(below 10%) were predictors of poor response. Responsewas evident within 1 month of starting HU therapy in themajority of responders. Thus, a short trial of HU therapy canpredict durable response.

Keywords Thalassemia intermedia . Hydroxyurea . HbFinduction

Introduction

Beta-thalassemia is the most commonly inherited blooddisorder in the world and results from a number of genetic

defects in β-globin gene expression [1]. It is a heteroge-neous group of disorders resulting from decreased β-globinproduction and a subsequent imbalance in the α/β-globinchain ratio. The excessα chains precipitate within red bloodcells (RBCs) resulting in hemolysis and ineffective eryth-ropoiesis. The phenotypic presentation varies in severitybased upon the imbalance of the α/β-globin chain ratio.Thalassemia major presents early in life with anemia and isgenerally transfusion dependent. On the other hand, β het-erozygous cases (thalassemia minor) are asymptomatic withnormal or only slightly reduced level of hemoglobin. Thal-assemia intermedia is an intermediate condition betweenthe two extremes (10% of cases), can have a homozygousor heterozygous inheritance pattern, is generally transfusionindependent or may require infrequent transfusion, and hasa clinically milder course than thalassemia major but severeenough compared to thalassemia minor [2].

Enhancing γ-globin chain synthesis within the RBCprecursors will reduce the α/non-α chain imbalance andcould potentially lead to an improvement in RBC survivalresulting in rise of hemoglobin levels. Pharmacologicalagents that increase γ-globin production, as evidenced byan increase in fetal hemoglobin (HbF), have been evaluatedas therapeutic agents for patients with β-thalassemia [3].Response to hydroxyurea (HU) has been most promisingbecause of the oral route, relatively inexpensive cost, andgood experience with the use on a long-term basis in otherdisorders [3]. Bradai et al. [8] used HU at 15–20 mg/kg perday in seven transfusion-dependent thalassemia major pa-tients and found that six of them became transfusion inde-pendent. The response persisted during the course of therapywith median follow-up duration of 19 months. Drugs likeHU are expected to have more beneficial effects in thal-assemia intermedia patients as the imbalance of the α/β-globin chain is lesser. However, the studies published so farhave been on a limited number of patients [7–20]. Hoppeet al. [16] treated five patients with thalassemia intermediawith HU and found significant beneficial effect in fourcases, three of which became transfusion independent. Wepresent our data on response to HU in 37 patients with thal-assemia intermedia.

A. Dixit . T. C. Chatterjee . P. Mishra . D. R. Choudhry .M. Mahapatra . S. Tyagi . M. Kabra . R. Saxena .V. P. Choudhry (*)Department of Haematology,All India Institute of Medical Sciences,New Delhi, Indiae-mail: vedpchoudhry@yahoo.co.inTel.: +91-11-26594670Fax: +91-11-26588663

Patients and methods

Thirty-seven consecutive patients attending the outpatientdepartment (OPD) of the Department of Hematology, AllIndia Institute of Medical Sciences (AIIMS), from Decem-ber 2001 to July 2003 were enrolled for the study. Writteninformed consent was obtained before the enrollment.

Inclusion criteria: diagnosis of thalassemia was based onquantification of HbF and HbA2 by high-performanceliquid chromatography (HPLC) including family studies.Thalassemia intermedia included cases of homozygous orheterozygous β-thalassemia and was defined as patientswho were:

1. Transfusion independent but had persistent anemia ofmore than 6 months duration with or without organo-megaly in the absence of intercurrent illness

2. Transfusion dependent but with a transfusion require-ment of less than four units per year to maintain hemo-globin above 80 g/l

3. Transfusion dependent and requiring more than fourunits per year; however, the transfusions startedafter the age of 5 years and/or were associated withhypersplenism

Exclusion criteria:

1. Cases of thalassemia intermedia with other than β-thalassemia genotype (for example, δβ-thalassemia,β-thalassemia heterozygous with structural hemoglo-binopathies)

2. Cases with preexisting renal or hepatic diseases3. Cases with positive serology for human immunodefi-

ciency virus (HIV), hepatitis B or C, or with chronicinfections (such as tuberculosis)

The median age of the patients was 10 years (range: 4–50 years). History of an affected family member was avail-able in nine cases (24.3%). The majority of the patients(17)were Punjabis ofwhom14weremigrants fromPakistanSindh province. Hemolytic facies was present in 23 patients(62%).All patients except one had some organomegalywithmean palpable liver span below the costal margin of 3.0±1.9 cm (range: 0–12 cm) and mean palpable spleen sizeof 5.2±2.6 cm (range: 0–12 cm) palpable below the leftcostal margin.

Mean hemoglobin before starting therapy was 65±12 g/l(range: 40–92 g/l). Fifteen cases (40%) were transfusionindependent, seven of which (18.9%) had never receivedany transfusion. Two cases did not require transfusion aftersplenectomy, and the remaining six cases required transfu-sion at presentation only, had stable hemoglobin of >60 g/lon folic acid supplementation, and refused further transfu-sions for personal reasons. The median age at receivingthe first transfusion was 6 years (range: 2–50 years). Ofthe transfusion-dependent patients, the median transfu-sion requirement was 4 units per year (range: 1–12 units)with four patients requiring >10 units a year, whereas thetransfusion requirement started after 5 years of age only.The median number of transfusions received before startingtherapywas 4 units (range 1–100 units).Mean serum ferritinlevel was 694.5±773.7 ng/ml (range: 80–3,600 ng/ml).Three patients were on chelation therapy with oral deferi-prone, and one patient refused chelation therapy for finan-cial reasons. Six patients (16.2%) had elevated HbA2 alsoalong with HbF, and two patients (5.4%) had raised HbA2alone without raised HbF (heterozygous β-thalassemia).

Red blood cell survival studies were performed in 20patients using 99Tc-labeled RBCs. The median RBC sur-vival was 12.5 days (range: 8–22 days). Three patients hadevidence of hypersplenism by nuclear scan two of whomwere enrolled after splenectomy and one patient refusedsplenectomy. Two more splenectomized patients whereRBC survival studies were not available were also enrolled.In all, four (10.5%) splenectomized patients entered thestudy.

Mutation analysis for five common β-thalassemia genesprevalent in the country and responsible for >90% of totalmutationswasperformed in27cases.Threepatients (11.1%)were negative for the five common mutations tested. Tenpatients (37%) were homozygous, eight (29.6%) were com-pound heterozygous, and six cases (22.2%) were heterozy-gous for these mutations. Distribution of various mutationsand XmnI polymorphism is given in Tables 1, 2.

Dose: hydroxyurea (Hydrea, Sarabhai) was given at10-mg/kg per day starting dose and increased by 5-mg/kgper day increments at 4-weekly intervals to a maximum of20 mg/kg per day or until the myelotoxicity appeared.

Toxicity: myelotoxicity was defined by absolute neutro-phil count (ANC) less than 1.5×109/l or platelet count lessthan 100×109/l. Hepatotoxicity and renal toxicity were de-

Table 1 Distribution of β-thal-assemia mutations among var-ious groups on HU

β-Thalassemia mutation Patients (n=27) Major responders(n=14)

Minor responders(n=7)

Nonresponders(n=6)

IVS 1-1(G-T)/IVS 1-1(G-T) 9 (33.3%) 4 4 1IVS 1-5(G-C)/IVS 1-5(G-C) 1 (3.7%) 1 0 0IVS 1-1(G-T)/619-bp deletion 3 (11.1%) 3 0 0IVS 1-1(G-T)/codon 8/9 (+G) 3 (11.1%) 2 1 0IVS I-5(G-C)/− (5 18.5%) 1 0 4619-bp deletion/− 1 (3.7%) 0 0 1IVS 1-1(G-T)/IVS 1-5(G-C) 2 (7.4%) 1 1 0No mutations identified 3 (11.1%) 2 1 0

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fined as more than twofold rise in alanine aminotransferase(ALT) or aspartate aminotransferase (AST) and as a >50%increase in serum creatinine concentration, respectively. Iftoxicity occurred, treatment was stopped until blood countsreturned to normal and then reintroduced at a lower dosewhich, if tolerated, was considered the maximum tolerateddose.

Duration of follow-up: minimum of 6 months of trialbefore considering a failure of response. Patients wereassessed earlier if a major response had already occurredand hemoglobin had stabilized for at least 2 months.

Themedian follow-up durationwas 12months (range: 4–36 months). Two patients required dose adjustments formyelotoxicity, and in one of them, the dose could be in-creased to 15 mg/kg per day. One patient developed milddiarrhea, which subsided by itself after 2 weeks. The re-maining patients tolerated the therapy well.

Laboratory monitoring: baseline hemoglobin and RBCindices were derived from the mean of three to four valuesover at least 6 months preceding the initiation of HU. Eval-uation of baseline HbF, HbA2, and F cells was done at least4 weeks after the last transfusion. All cases were screened forhepatitis B and C and HIV before starting the therapy. Otherstudies for enzymopathies [glucose-6-phosphate dehydro-genase (G6PD), pyruvate kinase (PK) deficiency], parox-ysmal nocturnal hemoglobinuria, and hereditary spherocytosiswere done wherever indicated.

Follow-up: complete blood counts (CBC) at 2-weeklyintervals until the maximum dose was reached and thenonce in 4 weeks; renal and liver function tests once every4 weeks until maximum dose and then every 8 weeks; HbF,

HbA2, and F cell estimation at the end of 6 months or afterthe major response.

Response criteria:

Major response: transfusion independent with final Hb>80 g/l in transfusion-dependent patients and a rise of≥2 g/l in transfusion-independent patientsMinor response: transfusion independent with rise inHb >20 g/l but final Hb <80 g/l or >50% decrease intransfusion requirement in transfusion-dependent pa-tients and rise in Hb between 10 and 20 g/l in trans-fusion-independent patientsNo response: rise in Hb <10 g/l in transfusion-inde-pendent patients and decrease in transfusion require-ment by <50% in transfusion-dependent patients

Laboratory methods: hemoglobin (Hb) estimation andtotal blood counts were done using an electronic counter(Sysmex K-4500, Kobe, Japan). Peripheral smear exami-nation was done for red cell morphology and presence ofnucleated RBCs. Reticulocyte count, serum iron studies,and other hematological tests were done as per standardmethods [4]. Serum ferritin was measured by immunomet-ric enzyme immunoassay using a standard kit (ORG 5FE,ORGENTEC Diagnostika GmbH, Mainz, Germany). HbFand HbA2 estimation was done by HPLC (Bio-Rad Variant,Hercules, Calif., USA). F cell estimation was done by themethod of Kleihauer-Betke et al. [4], and the percentageof F cells (number of F cells/100 RBCs on a smear) wascalculated.

Results

Twenty-six patients (70.2%) showed response to HUtherapy. Seventeen patients (45.9%) showed major re-sponse, and nine patients (24.3%) showed minor response.The median time to achieve first response was 2 months(range: 1–4 months), and the median time to reach peakresponse was 5 months (range: 2–8 months).

Major responders Of the major responders (17 patients)(45.9%), the median age was 10 years (range: 4–31 years).Table 3 shows the comparative parameters for the variousvariables before and after therapy. Mean rise in Hb was 25±7.1 g/l, and the difference between previous Hb and post-

Table 2 Distribution of XmnI polymorphism among various groupson HU therapy

XmnIpolymorphism

Patients(n=24)

Majorresponders(n=12)

Minorresponders(n=7)

Nonresponders(n=5)

+/+ 12 (50%) 5 5 2+/− 8

(33.3%)5 2 1

−/− 4(16.6%)

2 0 2

Table 3 Comparative data of major responders (n=17). NRBCs/100WBC nucleated red blood cells per 100 WBCs, Ret reticulocytes,MCVmean cell volume,MCHbmean cell hemoglobin,MCHCmean

cell hemoglobin concentration, RDW red cell distribution width andstandard deviation (SD)

Mean Hb(g/l)

NRBCs/100WBC

Ret(%)

MCV(fl)

MCHb(pg)

MCHC(g/l)

RDW(SD)

F cells(%)

HbF(%)

Pre-therapy

65±9(45–85)

14.6±27.7(1–105)

3.1±2.3(1–9.1)

71.7±1.7(58.9–90.8)

22.1±2.8(18.5–28.6)

311±17(284–335)

59.5±9.4(46.6–80.6)

72.4±18.4(45–92)

67.0±25.7(13.6–96)

Post-therapy

91±10(80–119)

4.2±8.5(0–36)

2.3±1.4(1–6)

74.0±9.2(57.5–88.7)

23.7±3.9(17.0–31.0)

321±18(290–352)

60.9±9.4(42.6–82.5)

81.7±18.2(55–99)

76.0±22.2(25.6–94.6)

p value <0.001 <0.05 <0.05 <0.05 <0.01 <0.05 >0.05 <0.01 <0.01

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therapy Hb was statistically significant (p<0.001). Meancell volume (MCV), mean cell hemoglobin (MCH), andmean cell hemoglobin concentration (MCHC) increasedon HU therapy, and this increment reached statistical sig-nificance. Mean reticulocyte count and nucleated red bloodcell (NRBC) count also decreased significantly on therapy.There was a rise in HbF levels and F cell percent duringthe therapy period, which was of statistical significance (p<0.01); however, this response was not uniform, and all pa-tients with a baseline HbF >85% showed a poor or no rise inHbF value despite a rise in total Hb levels. There was nosignificant difference in serum bilirubin levels and red celldistribution width (RDW) during therapy.

Three patients had a decrease in Hb levels with infec-tion, and one of them required transfusion once. Responseto HU was restored after control of infection and was main-tained thereafter. Eight patients witnessed a regression inthe degree of organomegaly after a median of 12 months oftherapy.

Minor responders Nine patients (24.3%) were minorresponders to HU therapy. Of these, two became transfusionindependent with rise of Hb of >20 g/l; however, the Hbremained below 80 g/l (73 and 75 g/l, respectively). Thecomparative data in this group are depicted in Table 4.

The mean rise in Hb was 18±9 g/l, which was of statis-tical significance (p<0.001). Mean nucleated RBCs andreticulocyte count decreased, and MCV and MCHb roseduring thecourseof therapy;however, thedifference reachedstatistical significance for MCVonly. There was no signif-icant change in MCHC and RDW during therapy. Mean F

cell count and HbF levels rose after starting HU therapy;however, unlike the major responders, the difference heredid not reach statistical significance. There was a poor cor-relation of HbF rise with total Hb rise in patients with base-line HbF of >85%, similar to major responders. One of thepatients was a major responder to begin with; however, Hbdecreased soon after the initial rise and was maintainedbelow 80 g/l subsequently.

NonrespondersAmongst the 11 nonresponders (29.7%), themedian age was 16 years (range: 4–50 years) with fourpatients >30 years of age. Twopatients aged 31 and 50years,respectively, had raised HbA2 levels only without rise inHbF levels at presentation; one of them was requiringrepeated transfusions. Another two patients had raisedHbA2along with raised HbF. Of the 11 patients, 4 had HbF below10%. The comparative parameters before and after therapyare depicted in Table 5.

Even in these patients, mean Hb rose from 65±15 g/l(range: 40–92 g/l) to 70±14 g/l, which was of statisticalsignificance for the transfusion-independent patients only.However, it was still below the set criteria for a meaningfulresponse and could have been a part of fluctuations in Hb inthese patients. There was a rise in MCV in transfusion-independent patients, which was statistically significant.The nucleated RBCs did come down (statistically insignif-icant), but there was no change in any other parameter.There was no significant difference in HbF levels and Fcell count before and after therapy; however, in one of thepatients, HbF rose from 12.2 to 27.7% without a rise intotal Hb.

Table 5 Comparative data of nonresponders (n=11). NRBCs/100WBC nucleated red blood cells per 100 WBCs, Ret reticulocytes,MCVmean cell volume,MCHbmean cell hemoglobin,MCHCmean

cell hemoglobin concentration, RDW red cell distribution width andstandard deviation (SD)

Mean Hb (g/l) NRBCs/100WBC

Ret (%) MCV (fl) MCHb (pg) MCHC (g/l) RDW (SD) F cells (%) HbF (%)

Pre-therapy

65±15(40–92)

7.2±10.1(0–30)

2.8±1.4(1.0–5.0)

68.8±2.5(63.3–72.6)

21.5±2.0(18.9–25.8)

314±23(270–365)

54.3±12.4(30.6–70.8)

36.2±40.8(2–90)

40.9±41.1(0.3–89.6)

Post-therapy

70±14(47–100)

5.1±6.6(0–23)

2.7±1.3(1.0–5.0)

71.2±4.2(65.0–79.4)

21.8±2.4(19.0–26.0)

311±17(268–328)

53.7±10.7(33.3–67.9)

36.2±40.8(2–90)

41.9±39.3(0.5–88.5)

p value <0.05a >0.0.5 >0.0.5 <0.0.5a >0.0.5 >0.0.5 >0.0.5 >0.0.5 >0.0.5aOnly in transfusion-independent patients

Table 4 Comparative data of minor responders (n=9). NRBCs/100WBC nucleated red blood cells per 100 WBCs, Ret reticulocytes,MCVmean cell volume,MCHbmean cell hemoglobin,MCHCmean

cell hemoglobin concentration, RDW red cell distribution width andstandard deviation (SD)

Mean Hb (g/l) NRBCs/100WBC

Ret (%) MCV (fl) MCHb (pg) MCHC (g/l) RDW (SD) F cells (%) HbF (%)

Pre-therapy

63±16(40–90)

4.2±3.0(1–10)

1.9±1.3(0.3–4.0)

70.6±4.7(62.7–79.0)

22.6±2.6(19.8–27.1)

316±31(248–350)

57.1±12.0(41.8–77.2)

74.3±26.1(35–99)

70.2±28.5(22.6–95.2)

Post-therapy

81±12(6.3–10.0)

3.0±1.5(0–5)

1.6±0.8(1–3)

73.6±3.0(68.8–78.8)

23.3±2.3(19.0–26.0)

316±23(260–338)

60.1±9.0(48.5–72.8)

84.0±17.9(58–100)

78.7±20.6(30.7–92.7)

p value <0.001 >0.05 >0.05 <0.05 >0.05 >0.05 >0.05 >0.05 >0.05

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There was no significant difference amongst the threegroups in terms of sex, transfusion dependence, number oftransfusions, age at first transfusion, and degree of orga-nomegaly or RBC survival. No significant difference wasfound amongst the groups for baseline average hemoglobin,leukocyte count, nucleated RBCs, reticulocyte count,MCV,MCH, MCHC, RDW, and unconjugated bilirubin either.Both responding groupswere comparable with regards to allof the parameters. However, there was a significant dif-ference in the age of patients in responding groups whencompared to the nonresponding group (p<0.05), which con-tained older patients (4 of 11 above 30 years of age). Meanbaseline HbF and F cell count was also higher in the re-sponding groups (both major and minor) when comparedindividually with the nonresponding group, which was sta-tistically significant (p<0.05). Two patients who had raisedHbA2 alone in the absence of raised HbF (heterozygous β-thalassemia) did not show any response to HU therapy.

No mutation was predictive of positive response to HUtherapy. However, IVS,1-5(G-C) in a heterozygous statewas more frequently associated with the nonrespondinggroup. Presence of XmnI polymorphism, though seen morecommonly in the responding groups than the nonrespond-ing group, did not reach statistical significance.

In 14 of 46 cases, both α- and β-thalassemia mutationswere studied: α-thalassemia mutations were found in fivecases and the remaining were negative. Three patients wereheterozygous for α3.7 deletion, and two had triplication ofthe α gene. In one of the patients with triplication of the αgene, β-thalassemia mutation was not available; however,thiswas a heterozygous thalassemia (with only raisedHbA2),and the association with α triplication might have been re-sponsible for the intermedia phenotype. He had jaundicewith low Hb (82 g/l) but was transfusion independent anddid not respond to HU therapy. The other patient with trip-lication of the α gene was negative for five common β-thalassemia mutations and was a minor responder to HUtherapy. Table 6 shows the interaction of these mutations.All patients with α3.7 del were major responders to HUtherapy. All patients with a response to HU and α-thalas-semia mutations also had XmnI polymorphism either homo-zygous or heterozygous.

Discussion

Patients with thalassemia intermedia are usually well com-pensated for their disease and pay the price in terms of in-creased morbidity from organomegaly, osteoporosis, and

other effects of exuberant extramedullary erythropoiesis.Hence, the decision to start these patients on a regular trans-fusion regimen is always difficult. Even a small rise in he-moglobin would be of immense value to suppress the highturnover of erythroid tissue and provide gratifying results.

Hydroxyurea produces fetal hemoglobin production via areactivation of γ genes as a result of some unknown mole-cular mechanisms. The clinical benefits of using this drug insickle cell anemia have already been demonstrated [5]. Sig-nificant benefit is also expected in severe β-thalassemiapatients because the increased production of γ chains canbalance the lack of β chains, can neutralize excess of αchains, and provides improvement. The beneficial results inthalassemia major patients have not been very encouraging[6–11]; however, many studies have documented goodresponse in thalassemia intermedia patients [12–19]. Mostof these studies included very small numbers of patients,and there was a need for a bigger study to prove the efficacyof HU in this group of patients.

We studied the response to HU in 37 patients and foundencouraging results. Overall, 26 patients (70.2%) showedresponse to HU therapy. Of these, 17 patients (45.9%)showed a major response. The response to HU therapy wasevident within 1 month of starting HU therapy in the ma-jority of patients. Only one patient had a delayed onset ofresponse at 4 months, and this patient was a minor re-sponder. Hence, response to HU can be predicted by a shorttrial (3 months) of therapy directly. Although most of thepatients showed stabilization of hemoglobin after 6 monthsof therapy, in some of the patients, peak effect was delayeduntil 8 months of therapy. There was no significant sideeffect other than myelotoxicity in two patients requiringdose adjustments. Most of the patients maintained their Hbon HU therapy (maximum follow-up up to 36 months);however, in three patients, Hb decreased after suffering anintercurrent illness, and in all of them, the response to HUwas restored after controlling the infection.

Table 7 Comparison of results of HU therapy with other publishedseries

Study Patients(n)

Response(major)

Response(minor)

Overallresponse

Hoppe et al.[16]

5 2 2 4 (80.0%)

de Paula et al.[9]

7 2 1 3 (42.8%)

Present study 37 17 9 26 (70.2%)

Table 6 α- and β-thalassemiamutations in thalassemia inter-media on HU

Patient α mutation β mutation XmnI Response to Hydrea

1 α3.7 del heterozygous IVS 1-1(G-T)/IVS 1-1(G-T) +/+ Major2 α3.7 del heterozygous IVS 1-1(G-T)/Fr 8-9(+G) +/− Major3 α3.7 del heterozygous IVS 1-1(G-T)/619 bp del +/− Major4 α triplication Negative +/− Minor5 α triplication Not done Not done Nonresponder

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No correlation of response to HU was found with β-thalassemiamutation; however, an increased association wasseen with XmnI polymorphism (statistically insignificant).Association with α3.7 deletion in the heterozygous state wasa predictor of good response to HU therapy; however, allcases with this mutation also had the presence of XmnIpolymorphism, suggesting a combination of variables af-fecting the final response. None of the patients with het-erozygous β-thalassemia who had raised HbA2 alone withthalassemia intermedia phenotype responded to HU, makingthis group of patients poor responders to HU therapy. One ofthese cases also had α triplication as a causative factor. Aninteresting observation was that the older age, low baselineF cell percent, and low HbF levels (particularly below 10%)were predictors of a poor response. In fact, none of the pa-tients with baseline HbF <10% showed any significantresponse to HU therapy. Mean HbF level rose on HU ther-apy significantly; however, there was no direct correlation ofdegree of response with the rise in HbF value in patientswith baseline HbF of >85%, suggesting that possibly thereare other mechanisms of action for HU as well. In fact,Zeng et al. [20] demonstrated that HU can increase α-, β-and γ-globin levels and hence may promote reduction inineffective erythropoiesis.

Our results are significant in terms of the strict definitionof response categorized as major or minor. In many studies,even a marginal rise in Hb was taken as evidence of re-sponse [12–19]. Table 7 shows the comparative data withother studies. Our study is the largest series of patients withthalassemia intermedia on HU therapy.

HU is a promising drug in the treatment of thalassemiaintermedia patients. A short trial of drug may determine thelikely responders to treatment and may improve the qualityof their life. However, its potential to cause leukemogenesisis still of concern.With more experience from the sickle cellpatients, this issue will also be addressed sooner or later.Studies on larger numbers of patients for longer durationof therapy are needed to evaluate its long-term safety andefficacy.

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