Evidence Table 16. Description of Hydroxyurea Toxicity in Randomized Controlled Trials in Diseases Other than Sickle Cell Disease

Author, yearLocationRecruitment start date - end dateInclusion and exclusion criteriaInterventionStarting dose*Jadad29 score
Frank, 2004104North AmericaOct 1996–Jan 1998Inclusion: Age >18; HIV+; ANC >1000/cmm, platelet >75,000/cmm; Hb >9.2g/dL for men, >8.8g/dL for women, CD4 200–700ddI 4
Exclusion: Preg; renal failure; liver failure; prior HU; pancreatitis; peripheral neuropathyHU (low dose) with/without ddI HU 1000 mg/d
HU (high dose) with/without ddIHU 1500 mg/d
Havlir, 2001 189North AmericaNov 1998 – Jul 1999Inclusion: Age >12 years; HIV+; at least 6 months on IDV, ZDV (or d4T), and 3TC); HIV RNA <200/ml; CD4 >200/ul, >100/ul prior to starting IDVHU IDV ddI d4T HU 600 BID 2
Exclusion: ANC <1000/ul; liver failure AST, ALT >3 ULT, documented or suspected hepatitis; prior treatment with HIV protease inhibitor other than IDV or both ddI and d4T; thrombocytopenia <75000/ul; anemia, <8.9 for female and 9.1 g/dl for men; history of grade 2 or greater peripheral neuropathyIDV ddI d4T + placebo
IDV ZDV (or d4T) 3TC
Swindells, 2005 111North AmericaSep 1999–Apr 2007Inclusion: Age >12; neutrophil count >1000; HIV-1 RNA between 400–100,000 and CD4 >100; failure of initial anti-retroviral treatment; had not received non-nucleoside reverse transcriptase inhibitors, ABC or ddI; Hb >9 for women >10 for men; plts > 75,000; estimated creatinine clearance >50mL/min, serum lipase <ULN, serum amylase <1.5× ULN, ALT<5× ULNABC/EFV/ ddI and HU HU 500 mg BID 2
Exclusion: Preg or breast feeding; acute hepatitis within 6 months; immunotherapeutic vaccine or cytotoxic agents within 8 wks before start of study; hx of pancreatitis or peripheral neuropathy within 2 mo before study startABC/EFV/ ddI
Beeson, 1999 190EuropeJun 2005 – Jun 2005Inclusion: Hb >10g/dL; normal amylase; neutrophil >1500/mcl; included if leucopenia; included if plt >150k/mcl; absence of current HIV-associated disease or prior hx of any AIDS-defining illnessddI + HU HU 500 mg BID 3
Bloch, 2006 191AustraliaJan 2000 – Feb 2002Inclusion: acute primary HIV infectionIDV/RTV/ddI + either stavudine or lamiduvine + HU HU 500 mg BID 2
IDV/RTV/ddI + either stavudine or lamiduvine
Rutschmann Cluster/ HIV
Rutschmann, 1998 192EuropeInclusion: Age ≥ 20 years; HIV+; CD4 from >200 to <500 (twice); two HIV RNA >1000/mlddI/d4T/HUHU 500 mg bid 3
Exclusion: prior HU; pancreatitis; alcohol; peripheral neuropathy; use of d4TddI/stavudine + placebo
Rutschmann, 1998 193EuropeInclusion: HIV+; CD4 200–500/ul; HIV RNA >1000/ml; staveudine and HU naïveddI/stavudine/HU§HU 500 mg BID 1
Exclusion: > 6 months of ddIddI/stavudine
Rutschmann, 2000194EuropeInclusion: CD4 between 2---500; HIV RNA >1000 ×2ddI/stavudine/HU HU 500 mg BID 2
Exclusion: prior HU; prior stavudine; ddI >6 monthsPlacebo, ddI stavudine
Hehlmann, 2003 113EuropeFeb 1991 – Dec 1994Inclusion: newly diagnosed CML in chronic phaseHU 40mg/kg/d 2
Exclusion: prior therapyIFN-alpha 2a + HUIFN 5*106IU/m2/d + HU added as required
no author, 1998 115EuropeDec 1987–Dec 1992Inclusion: Age ≥ 18; previously untreated, newly diagnosed Ph+ CML in chronic phase; BCR-ABL (+); WHO performance status 0,1, or 2; adequate renal/hepatic fxn (bilirubin and creatinine <2× ULN)HU NR 2
Exclusion: cytogenetic abnl other than -y, +8 or second 22q-IFN and HU if needed3 million units 5×/wk
Hehlmann, 1994 114EuropeJul 1983 – Jan 1991Inclusion: newly diagnosed, not pretreated CML in chronic phase; fatigue or weight loss or fever or organomegaly-related symptoms or WBC >50,000 or Thrombocytosis >1 million exclusion, Ph(-) or unknown Ph statusHU 40mg/kg/d 3
IFN 4 million units/m2
Broustet, 1991 116EuropeMay 1987 – Jul 1990Inclusion; Age >18; Ph+ CMLHU 3
Exclusion: prior chemo; trisomy 8, isochromosome 17, double Ph+IFN4 million units/m2
Hehlmann, 1993 195EuropeJul 1983 – Jan 1991Inclusion: newly diagnosed CML in chronic phaseHU 40 mg/kg/d 2
Exclusion: not in chronic phase; no treatment required; prior treatment with IFN or irradiation or cytostatics; lack of consent; second neoplasia; any other reason that made treatment with protocol unlikelyBusulfan0.1 mg/kg/d
Solid Tumor
Stephens, 1984 121North AmericaInclusion: advanced prostate cancer (stage D disease)HU 3600mg/m2, 2days/week 2
Exclusion: unstable ischemic or rheumatic heart disease; heart failureAdriamycin + cyclophosphamideAdriamycin at 40 mg/mˆ2 and cyclophosphamide at 200 mg/m2; reduced to AC 20+cyclophosphamide 100 if in poor-risk group
Loening, 1981 122North AmericaMay 1977 – Apr 1979Inclusion: histologically proven prostate CA with distant mets and progressionHU 3g/m22
Cyclophosphamide 1g/m2
Najean Cluster/ PV
Najean, 1997 123EuropeMay 1997–Jun 2005Exclusion: age > 65 excluded; previous treatment with radiotherapy; previous treatment with chemotherapyHU 25 mg/kg/d 2
Pipobroman 1.25 mg/kg/d
Kiladjian, 2006103HU 1
Harrison, 2005 131EuropeAug 1997 – Aug 2002Inclusion: Age at least 18 yr with ETHU + aspirin 75mg/d HU: 0.5–1g/d 2
Anagrelide + aspirin 75mg/danagrelide 0.5mg BID
Finazzi Cluster/ET
Finazzi, 2000 130Europe1990-1993Inclusion: ET; high risk of thrombosis (>60 yrs or prior thrombosis)HU 15mg/kg 2
No myelosuppressive agent at randomization
Cortelazzo, 1995 129EuropeApr 1990 – Aug 1993Inclusion: Age >60; previous thrombosis; plt count <1.5 millionHU 15 mg/kg 2

In HIV only HU doses are given

This was a five-arm study but adverse event data is given for three arms due to pooling of some arms. Treatments naive as well as treatment experienced patients are included. Baseline data is reported for all groups combined (listed in Arm 1) and stated to be similar between arms.

Randomized for 12 weeks then switched to open-label according to patient response in the first 12 weeks.


Many patients crossed over after the 12 week-blinding was removed. If they had a poor response (viral load>200/ml) patients were permitted to start HU or dropped if already in HU arm. The HU arm had 34 responders, 24 crossovers after 3 months and 19 remained in the “placebo” arm.

See Rutschmann, 1998102 for other details of inclusion criteria, this is the same report after 24 months (instead of 12 months)

This is a follow-up of the previous Najean trial123. Very limited data is given on patients.


Many patients from the placebo group crossed over to HU. 79 received HU alone, 15 received HU and busulfan, and 20 received no chemotherapy.

3TC = Lamivudine; ABC = abacavir; Abnl = abnormal; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate transaminase; BID = twice a day; CA = cancer; CCNU = Lomustine; CML = chronic myelogenous leukemia; d4T = Didehydrodeoxythymidine; ddI = didanosine; EFV = efavirenz; ET = essential thrombocytopenia; Fxn = function; HIV = human immunodeficiency virus; HU = hydroxyurea; hx = history; IDV = indinavir; IFN = interferon; mets = metastases; NR = not reported; Ph = Philadelphia; plt = platelet; preg = pregnancy; PV = polycythemia vera; RNA = ribonucleic acid; RTV=ritonavir; ULN = upper limit of normal; ULT = upper limit; WBC = white blood cells; WHO = World Health Organization; ZDV = zidovudine.

From: Appendix C: Evidence Tables

Cover of Hydroxyurea for the Treatment of Sickle Cell Disease
Hydroxyurea for the Treatment of Sickle Cell Disease.
Evidence Reports/Technology Assessments, No. 165.
Segal JB, Strouse JJ, Beach MC, et al.

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