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PubMed1998

Successful treatment of accelerated and blastic phase of chronic myeloid leukemia with high-dose interferon-alpha combined with hydroxyurea.

Transformed chronic myeloid leukemia (CML) has a dismal prognosis, and treatment with a variety of chemotherapeutic agents is extremely disappointing. A novel therapeutic approach was initiated to improve the outcome of this condition. Nine patients, four females and five males, with either acceleration of CML or blast crisis (myeloid), or, in two instances, both, entered this pilot study. Median age was 60 years; seven patients were Philadelphia chromosome positive; two were negative but showed a bcr/abl rearrangement. All patients had a well-defined preceding period of stable chronic phase, for which they received sequentially hydroxyurea (N = 9), interferon (IFN) (N = 3), busulfan (N = 2), melphalan (N = 1), 6-MP (N = 1), or allogeneic BMT (N = 1). Median length of preceding chronic phase to acceleration or blast crisis was 56 months. All patients responded to treatment with a starting dose of IFN (9 Mio U/day), subcutaneously, and hydroxyurea (3 g/day), orally, by reversal to chronic phase. Three of the patients responded repeatedly during their course of disease. Median time for reversal to chronic phase was 4 weeks. Adverse side effects like nausea, vomiting, hair loss, fever, and prolonged cytopenia as seen after chemotherapy were not observed. The duration of chronic phase varied, and lasted, in six instances, more than 5 months, while the Philadelphia chromosome persisted. One additional patient received an unrelated bone marrow transplantation after reaching chronic phase (+24 months). Disease progression occurred 2 months after cessation of treatment. This treatment has proven very promising so far.

Adult↗

PubMed2006

Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia.

Despite recent discoveries made in myeloproliferative disorders other than chronic myelogenous leukemia, which it is hoped will result in earlier diagnosis, and better evaluation and management of patients, hematological evolution to myelofibrosis, acute leukemia, and myelodysplastic syndromes (AL/MDS) remain major causes of long-term mortality in polycythemia vera (PV) and essential thrombocythemia (ET) patients. Evaluation of long-term leukemogenic risk of currently available drugs, therefore, is crucial. We report updated results of three French prospective trials of hydroxyurea and pipobroman in PV and ET patients with a median follow-up longer than 10 years. The results show that the incidence of AL/MDS is higher than previously reported with no evidence of a plateau (with approximately 40% of AL/MDS cases occurring after the 12th year of follow-up). Although hydroxyurea currently remains the first choice in the treatment of high-risk PV and ET patients, the use of nonleukemogenic drugs, such as interferon alpha (IFN-alpha) or anagrelide, should be assessed more widely in randomized trials using accurate diagnostic criteria and taking into account the presence of the JAK2 mutation, given that they may have an impact on disease evolution.

Antineoplastic Agents, Alkylating↗

PubMed1985

Stimulation of F-cell production in patients with sickle-cell anemia treated with cytarabine or hydroxyurea.

To investigate the mechanism of pharmacologic stimulation of fetal hemoglobin in sickle-cell anemia (hemoglobin S disease), we treated two patients with homozygous disease with various doses of cytarabine (also known as Ara-C) or hydroxyurea and evaluated the effects of each treatment on F-reticulocyte production and on hemopoiesis. The treatments stimulated F-cell production in a dose-related fashion. Treatments that increased F-cell production also increased the patient's hematocrit and caused only minor, transient decreases in white cells. The main effect on erythropoiesis consisted of cytoreduction of the mature erythron (as assessed by measurements of reticulocytes) or a decrease in the compartment of erythroid progenitors (colony-forming units--erythroid and burst-forming units--erythroid). The reduction phase was followed by reticulocyte regeneration, during which most of the increase in the absolute numbers of F reticulocytes took place. Lower doses of cytarabine or hydroxyurea resulted in smaller waves of reticulocyte regeneration and lesser effects on F-reticulocyte production. These results suggest that the main cause of stimulation of fetal hemoglobin in patients with sickle-cell anemia treated with cell cycle-specific compounds is the erythroid regeneration triggered by the drug treatment.

Adult↗

PubMed1986

Preliminary observations on the therapy of the myeloid blast phase of chronic granulocytic leukemia with plicamycin and hydroxyurea.

We observed a dramatic improvement in the peripheral blood counts of a patient in the myeloid blast phase of chronic granulocytic leukemia after plicamycin (mithramycin) therapy of concurrent hypercalcemia. We then treated eight additional patients in the blast phase of chronic granulocytic leukemia with a combination of alternate-day plicamycin and daily hydroxyurea. All six patients with myeloid morphology at the time of blast crisis responded with a return to a chronic phase without an intervening pancytopenic period. Of three patients with lymphoid morphology at the time of treatment, only one responded (this patient had recently relapsed and converted from myeloid to lymphoid morphology). Another patient with nonmyeloid, nonlymphoid blast morphology also did not respond. Continual therapy with the two-drug combination appeared to be necessary, since early relapses were seen in responding patients whose therapy was interrupted. These data are preliminary and will need further confirmation, but they suggest that the combination of alternate-day plicamycin and daily hydroxyurea may be effective in the myeloid blast phase of chronic granulocytic leukemia.

Adult↗

PubMed2001

Healing of an MRSA-colonized, hydroxyurea-induced leg ulcer with honey.

BACKGROUND: With the everincreasing emergence of antibiotic-resistant pathogens, in particular methicillin-resistant Staphylococcus aureus (MRSA) in leg ulcers, a means of reducing the bacterial bioburden of such ulcers, other than by the use of either topical or systemic antibiotics, is urgently required. METHODS: We report the case of an immunosuppressed patient who developed a hydroxyurea-induced leg ulcer with subclinical MRSA infection which was subsequently treated with topical application of manuka honey, without cessation of hydroxyurea or cyclosporin. RESULTS: MRSA was eradicated from the ulcer and rapid healing was successfully achieved. CONCLUSION: Honey is recognized to have antibacterial properties, and can also promote effective wound healing. A traditional therapy, therefore, appears to have enormous potential in solving new problems.

Administration, Topical↗

PubMed2003

Successful treatment of recalcitrant psoriasis with a combination of infliximab and hydroxyurea.

We report the use of a combination of the tumour necrosis factor alpha (TNF alpha) inhibitor infliximab and hydroxyurea to achieve control of disabling psoriasis and psoriatic arthritis. Our patient had psoriasis that proved resistant to conventional therapy including vitamin D analogues, topical steroids, dithranol, crude coal tar, narrow band UVB, bath PUVA and acitretin. She subsequently responded to hydroxyurea 1 g daily combined with infliximab infusions repeated at three monthly intervals which led to satisfactory control of her psoriasis and psoriatic arthritis. She has not reported any side-effects from this treatment regimen and her full blood count has remained normal.

Administration, Oral↗

PubMed2004

Plasma cell leukemia occurring in a patient with thrombocythemia treated with hydroxyurea and busulphan.

Plasma cell leukemia (PCL) is a rare aggressive lymphoproliferative disease with a short median survival and a very poor prognosis. We report the case of a 63-year-old man who developed a PCL after 5 years of chemotherapy with hydroxyurea and busulphan for Essential thrombocythemia (ET). The karyotype showed a deletion of chromosome 7 and the plasma cells cytofluorimetric examination revealed a high expression of Multidrug Resistance related P-glycoprotein (PGP). After the second cycle of VAD chemotherapy the patient had a severe pneumonia and died with refractory PCL. This is a rare example of the coexistence of a chronic myeloproliferative and lymphoproliferative diseases in the same patient, and to the best of our knowledge, the first reported in the literature involving PCL and ET. Moreover, this case shows the possibility of secondary malignancies developing in patients treated with busulphan and hydroxyurea for chronic myeloproliferative disorders.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Effects of thio-tepa and hydroxyurea on sperm production in Lakeview hamsters.

The spermatogenic cell sensitivity in the induction of sperm abnormalities by two antineoplastic agents, thio-TEPA and hydroxyurea in inbred Lakeview hamsters was studied and the results were compared with those of similar investigations with mice. Testis weights, epididymal sperm numbers, and body weights were also monitored up to 12 wk after treatment. Thio-TEPA administration increased sperm abnormalities and reduced testis weights as well as sperm numbers in a dose-dependent manner at wk 4 and 12 after treatment. Hydroxyurea administration was ineffective in inducing sperm abnormalities, but testis weights and sperm numbers were adversely affected dose-dependent changes in body weights after treatment with either agent were also recorded. The findings with thio-TEPA on sperm morphology agree with those reported for the mouse. However, unlike the results of the mouse studies, hydroxy-urea effects on sperm shape were not observed in the hamster.

Animals↗

PubMed1982

Comparison of teratogenic effects of aspirin and hydroxyurea in the Fischer 344 and Wistar strains.

The Fischer 344 rat is being used increasingly in toxicology studies. There have been few reports in which rats of this strain were used in teratology and reproduction studies, but comparison of teratologic data with other toxic and points and kinetic information would be greatly facilitated by using the same strain. Therefore, the embryotoxic effects of two positive teratogens, aspirin and hydroxyurea, were compared in Fischer rats and in the commonly used Wistar rats. Aspirin was administered in single oral doses of 500 and 625 mg/kg on d 10; hydroxyurea was injected ip at 500 mg/kg on d 11. Dams were sacrificed on d 20 and fetuses examined for skeletal and visceral defects. Male and female fetal weights and lengths were significantly reduced in treated groups in both strains. Both teratogens caused a significant increase in resorptions in Wistar and Fischer rats. A wide variety of skeletal alterations were induced by both teratogens in both strains. These included extra ribs, fused or missing ribs, extra thoracic and lumbar vertebrae, split vertebral centra, and missing vertebrae. Only a small number of Fischer fetuses exhibited visceral malformations such as hydrocephaly and cleft palate. The frequency of soft-tissue malformations, including cleft palate and severe cardiac anomalies, was much higher in Wistar fetuses.

Abnormalities, Drug-Induced↗

PubMed2005

Clinical and laboratory effects of hydroxyurea in children and adolescents with sickle cell anemia: a Portuguese hospital study.

Our aim was to assess the efficacy and safety of hydroxyurea (HU) in children with severe forms of sickle cell anemia followed in a Portuguese hospital. We carried out an open-label uncontrolled prospective study, which included children with severe forms of sickle cell anemia. Hydroxyurea was started at 15 mg/kg/day and increased to a maximum dose of 25 mg/kg/day. Patients were monitored to assess compliance, clinical and hematological response and toxicity. Nine children and adolescents, five girls and four boys, with a median age of 13 years (range 8 to 16) were enrolled in the study during a period of 24 months. All patients completed at least 15 months of therapy. Hb F was significantly increased, from a mean of 7.0 +/- 3.9% to 13.7 +/- 5.3% (p = 0.028). Clinically, all patients responded significantly with a reduction of 80% in the number of vaso-occlusive crises (VOC), 69% in hospital admissions, 76% in hospitalization days and 67% in transfusion requirements, without significant toxicity. We concluded that, in our population, HU proved to be effective in increasing Hb F levels, and in decreasing hospitalizations for VOC and transfusion requirements with no major side effects. Long-term clinical follow-up is important to certify benefit maintenance.

Adolescent↗

PubMed1998

Eradication of latent Epstein-Barr virus by hydroxyurea alters the growth-transformed cell phenotype.

The hallmark of infection by human herpesviruses, life-long persistence in the host, is unaffected by current antiviral therapies effective against replication of virus. In vitro studies indicated that low concentrations of the ribonucleotide reductase inhibitor, hydroxyurea, completely eliminated Epstein-Barr virus (EBV) episomes from latently infected Burkitt's lymphoma (BL) cell subsets, providing the first example of chemotherapeutic eradication of a latent herpesvirus from any cell population. Unlike parental EBV-positive BL cells, virus-free cell progeny from one treated cell line no longer exhibited the malignant phenotype in tumorigenicity assays. Hydroxyurea-treated primary B lymphocytes immortalized by EBV ceased to proliferate as episomes were lost. The altered growth phenotype of both BL cells and immortalized primary B cells suggests that latent EBV is an appropriate and accessible therapeutic target for treatment of some EBV-induced lymphoproliferations.

Animals↗

PubMed2006

Paclitaxel, 5-fluorouracil and hydroxyurea concurrent with radiation in locally advanced nasopharyngeal carcinoma.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is the standard treatment for locally advanced nasopharyngeal carcinoma (NPC). We conducted a phase II trial using paclitaxel, 5-fluorouracil and hydroxyurea concurrent with radiation (TFHX). PATIENTS AND METHODS: Fifty-nine patients with locally advanced NPC were treated with CRT consisting of 4-day continuous infusions of paclitaxel (20 mg/m(2)/d) and 5-fluorouracil (600 mg/m(2)/d), and oral hydroxyurea 500 mg bid for nine doses, every 3 weeks concurrent with radiotherapy (RT). RT consisted of once daily 200cGy fractions 5 times per week to a total of 7000cGy. RESULTS: Complete response was seen in 86% and 71% of patients at 4 and 12 months after CRT. The median follow-up was 34 months. Twenty-three patients experienced relapse. Sixteen deaths occurred: 13 from progressive disease. Three-year overall survival and progression-free survival were 72% and 54% respectively, with locoregional and distant control rates of 83% and 64% at 3 years respectively. Grade 3 to 4 acute toxicities included oropharyngeal mucositis in 81% of patients treated, dermatitis in 63%, weight loss in 32%, and neutropenia in 22%. Neutropenic fever was seen in 14%. There were no treatment-related deaths from acute toxicity. CONCLUSIONS: TFHX is shown to be feasible in NPC. Non-cross resistant induction chemotherapy should be further studied with this regimen.

Adult↗

PubMed1996

Treatment of human immunodeficiency virus infection with hydroxyurea: virologic and clinical evaluation.

To assess the efficacy of the therapeutic use of inhibitors of ribonucleotide reductase for the treatment of human immunodeficiency virus (HIV) type 1 infection, 7 consecutive patients were enrolled in a clinical trial involving monotherapy with hydroxyurea for 8-19 weeks. During therapy, patients were evaluated for clinical status and immunologic, hematologic, and quantitative virologic parameters, including determinations of viremia and the number of provirus-containing cells by competitive polymerase chain reaction. In all patients, these parameters were not modified during the course of therapy. The number of CD4 cells remained generally unchanged or showed a tendency to further decline. No sign of improvement in HIV disease was detected in any patient. These observations indicate that monotherapy with hydroxyurea does not provide therapeutic benefit to HIV-1-infected patients.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Weekly levofolinic acid and 5-fluorouracil plus hydroxyurea in metastatic gastrointestinal adenocarcinomas.

There were 42 patients with advanced gastrointestinal carcinomas (GA) enrolled in the study. In the Phase I part of the study we identified the MTD of 5-fluorouracil (5FU) in combination with levofolinic acid 100 mg/m2 per week intravenously plus hydroxyurea 1 g/m2 per week given by mouth in 3 refracted doses starting 6 hours after 5FU was administered. This treatment was given weekly for 6 consecutive weeks followed by a 15-day rest period. We were not able to increase 5FU weekly dosage above 700 mg/m2 due to the occurrence of grade 3-4 gastrointestinal toxicity. Thus 5FU was employed at 600 mg/m2 per week for the Phase II part of the study. Among 20 evaluable patients with measurable metastatic colorectal cancer, 1 patient had CR of 6.0+ months and 7 patients had PR with a mean duration of 6.2+ months, for an overall response rate of 40%. Four patients (20%) showed stable disease, and 8 patients progressed. The mean survival of the whole group was 5+ months (range: 3.0-12.8). This treatment was very well tolerated by most patients, with grade 3 diarrhea in 10% of cases and grade 3 vomiting in 20% of patients. Hydroxyurea (HU), employed at this dosage, seems not to increase 5FU/FA-related toxicity. This regimen is quite active in the management of advanced colorectal carcinoma, and may be safely given on an out-patient basis. A Phase III randomized trial may be established if HU improves results achievable with the 5FU-FA combination.

Adenocarcinoma↗

PubMed2001

Phase I and pharmacologic study of i.v. hydroxyurea infusion given with i.p. 5-fluoro-2'-deoxyuridine and leucovorin.

Preclinical data suggests that the action of fluoropyrimidines may be enhanced by the addition of hydroxyurea. We developed a phase I trial to determine the maximum tolerated dose and pharmacokinetics of i.v. hydroxyurea (HU) in combination with i.p. 5-fluoro-2'-deoxyuridine (FUdR) and leucovorin (LV). Eligible patients had metastatic carcinoma confined mostly to the peritoneal cavity, and adequate hepatic, renal and bone marrow function. Patients were treated with a fixed dose of FUdR (3 g) and LV (640 mg) administered on days 1--3. HU was administered as a 72-h infusion starting simultaneously with i.p. therapy on day 1. The following dose levels were studied: 2.0, 2.5, 3.0 and 3.6 g/m(2)/day. Pharmacokinetics were studied in blood and peritoneal fluid. Twenty-eight patients were accrued. Steady-state plasma and peritoneal fluid HU levels increased with increasing dose, and steady state was achieved within 12 h of continuous dosing. The steady-state HU plasma:peritoneal fluid concentration ratio ranged from 1.06 x 10(3) to 1.25 x 10(3) and the plasma HU clearance ranged from 4.63 to 5.81 l/h/m(2). Peritoneal fluid AUC = 137,639 +/- 43,914 microg/ml x min, t(1/2) = 100.9 +/- 56.4 min and Cl = 25.29 +/- 10.88 ml/min. Neutropenia represented the dose-limiting toxicity. We conclude that i.p. FUdR and LV in combination with i.v. HU is well tolerated. The addition of systemic HU increased the incidence of myelosuppression.

Adult↗

PubMed2004

Enhanced HIV-specific immune responses in chronically HIV-infected patients receiving didanosine plus hydroxyurea.

BACKGROUND: The role of hydroxyurea (HU) in the treatment of HIV infection remains controversial. HU potentiates didanosine (ddI) antiviral activity and might exert immunomodulatory effects. PATIENTS AND METHODS: Immunologic parameters were examined in HIV-infected patients enrolled in a simplification trial in which ddI-HU was provided to subjects who had been on complete virus suppression under highly active antiretroviral therapy (HAART) for longer than 6 months. A total of 84 of these patients showed plasma viraemia repeatedly below 5000 HIV-RNA copies/ml, and were the main study population. A group of 22 patients who continued on HAART and another of 22 drug-naive HIV-positive individuals were taken as controls. RESULTS: At 12 months, the levels of naive and memory T-cell subsets were similar in patients on ddI-HU and under HAART, whereas immune activation tended to be lower in the former group. The frequency of HIV-specific CD8+ T cells (CTL) directed against 125 peptides derived from Gag, Pol, Env, Nef and HIV regulatory proteins was similar among patients on ddI-HU and untreated controls, and significantly higher than in patients under HAART. This higher CTL response in patients on ddI-HU was seen even when considering only subjects with undetectable viral load. HIV-specific CD4+ T-cell responses were absent in almost all patients on HAART, whereas they were present in up to 19% of patients on ddI-HU. CONCLUSION: Treatment with ddI-HU provides higher levels of HIV-specific CD8+ and CD4+ T-cell responses than standard triple drug regimens. Thus, hydroxyurea might exert a beneficial immunomodulatory effect in HIV infection.

Anti-HIV Agents↗

PubMed2003

Resolution of chronic hepatic sequestration in a patient with homozygous sickle cell disease receiving hydroxyurea.

Hepatic sequestration is an uncommon complication in patients with homozygous sickle cell disease. Although transfusion therapy has been effective for the acute condition, no definitive treatment of chronic hepatic sequestration has been identified. We describe a 17-year-old male patient with hemoglobin SS and chronic hepatic sequestration who was treated with long-term (60 months) hydroxyurea. After 36 months of HU therapy, the patient had both an excellent hematologic response and a resolution of hepatic sequestration, as evidenced by disappearance of clinical hepatomegaly, normalization of liver volume on serial computed tomography scans, as well as decreased sinusoidal dilatation and congestion and red blood cell sickling on liver biopsy. The findings in this case suggest that hydroxyurea may benefit patients who have unusual complications of sickle cell disease, such as chronic erythrocyte sickling in the liver.

Adolescent↗

PubMedDate not supplied

Phase I study of concomitant chemoradiotherapy with irinotecan, 5-FU, and hydroxyurea for patients with advanced and/or recurrent head and neck cancer.

PURPOSE: We sought to investigate CPT-11 as a promising agent to our established regimen of 5-fluorouracil (5-FU), hydroxyurea, and hyperfractionated radiation therapy. A phase I study was conducted to determine the maximum tolerated dose and dose-limiting toxicities of this regimen. PATIENTS AND METHODS: Eligible patients included patients with poor prognosis advanced head and neck cancer who required radiation therapy. All patients were treated on a 14-day cycle. Each patient received 5-FU (600 mg/m(2)/d), hydroxyurea (500 mg orally every 12 hours), radiation therapy twice daily (150 cGy each fraction), and CPT-11 at a starting dose of 5 mg/m(2)/d for 5 consecutive days followed by a 9-day break. CPT-11 was escalated in five mg/m(2)/d increments. Dose-limiting toxicity was defined as grade 4 hematologic toxicity, persistent grade 4 dermatitis and mucositis, grade 4 diarrhea despite maximal pharmacologic intervention, and inability to receive full-dose chemotherapy with the next cycle of treatment. Fourteen patients were treated at maximum tolerated dose to verify the recommended phase II dose. RESULTS: Between August 1998 and August 2001, 31 patients with advanced and/or recurrent head and neck cancer were enrolled. Cohorts of nine, four, three, and 14 patients were treated at 5-, 10-, 15-, and 10-mg/m(2)/d dose levels of CPT-11. The 5- and 10-mg/m(2)/d dose levels were well tolerated All three patients treated at 15 mg/m(2)/d experienced neutropenic dose-limiting toxicity during cycles 1-2. DISCUSSION: The maximum tolerated dose and recommended phase II dose of CPT-11 with hyperfractionated radiation therapy is 10 mg/m(2)/d.

Adult↗