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Ruxolitinib, a potent JAK1/JAK2 inhibitor, was found to be superior to the best available therapy (BAT) in controlling hematocrit, reducing splenomegaly, and improving symptoms in the phase 3 RESPONSE study of patients with polycythemia vera with splenomegaly who experienced an inadequate response to or adverse effects from hydroxyurea. We report findings from a subgroup analysis of Japanese patients in RESPONSE (n = 18). The composite response rate (hematocrit control and spleen response) was higher in patients receiving ruxolitinib (50.0%) than in those receiving BAT (8.3%). A total of 50.0% of patients randomized to ruxolitinib achieved a spleen response vs 8.3% of those receiving BAT; 100 and 33.3% of patients in the respective groups achieved hematocrit control, with mean hematocrit in ruxolitinib-treated patients remaining stable at < 45% throughout the study. Similarly, a higher proportion of ruxolitinib-treated patients achieved complete hematologic remission (33.3 vs 16.7%). Ruxolitinib also led to rapid improvements in pruritus. All responses with ruxolitinib were durable to week 80, and its safety profile was consistent with that in the overall study. These findings suggest that ruxolitinib is an effective and well-tolerated treatment option for Japanese patients with polycythemia vera with an inadequate response to or adverse effects from hydroxyurea.

Ruxolitinib (Rux), a JAK1/2 inhibitor, has been approved for patients with myelofibrosis and in polycythemia vera with inadequate response/intolerance to hydroxycarbamide. Studies have demonstrated that Rux improves disease-related symptoms and splenomegaly. A late emerging observation from two Phase III trials was that Rux was associated with survival advantage in comparison with placebo or other available therapies in myelofibrosis. Important data suggest that for polycythemia vera Rux improved control of blood counts. Main hematological side effects are anemia and thrombocytopenia predominantly at the beginning of the treatment. Some studies and case reports highlighted potential risks of nonmelanoma skin cancers and increased risk of infection including reactivation of hepatitis B, tuberculosis or herpes zoster infections after Rux treatment.

Hemoglobin E-beta thalassemia (Hb E/β-thalassemia) is a distinct, yet common, type of β-thalassemia, in which the patient co-inherits a β-thalassemia allele from one parent, and a structural variant, Hb E, from the other parent. This co-inheritance leads to remarkable clinical heterogeneity, varying degrees of chronic anemia, and a wide spectrum of complications due to ineffective erythropoiesis and iron overload. Hydroxyurea (HU), an oral chemotherapeutic drug, is expected to decrease disease severity. To assess the clinical efficacy and safety of HU in Hb E/β-thalassemia patients. We searched MEDLINE, EMBASE, Cochrane databases, and major preceding conferences for studies that assessed HU in Hb E/β-thalassemias patients. The effect size was estimated as a proportion (responder/sample size). Qualities of eligible studies were assessed using NIH tools. A total of five [one randomized clinical trial (RCT) and four observational] studies involving 106 patients were included. HU was associated with a significant RR of 46% with no statistical heterogeneity. No serious adverse effects were reported. Patients with Hb E/β-thalassemia may benefit from a trial of HU, though large RCTs assessing efficacy should be conducted to confirm the findings of this meta-analysis and to assess long-term toxicity and response sustainability.

Background: Hydroxyurea is an antimetabolite primarily used to treat myeloproliferative disorders, and chronic treatment is associated with many cutaneous adverse effects ranging in severity from ichthyosis to aggressive nonmelanoma skin cancer., Case Presentation: We report a 67-year-oldman with a history of polycythemia vera who was referred for management of progressively worsening dorsal hand lesions. The patient presented withhyperpigmentation, ichthyosis, plantar keratoderma, dermatomyositis-like eruptions, two squamous cell carcinomas, and actinic keratoses. The adversereactions observed were acknowledged to be related to chronic hydroxyurea use. The patient underwent Mohs excision of the squamous cell carcinomas and thehydroxyurea was promptly discontinued; subsequent cutaneous improvement of the dermatomyositislike lesions ensued. Another clinically suspicious aggressive squamous cell carcinoma was suspected and the patient was referred to the plastic surgery department for complete excision because of the size of the lesion. The patient remains on periodic dermatology follow up., Conclusions: We report a case that exemplifies the cutaneous adverse effects of chronic hydroxyurea therapy. Although many cases improve after drug discontinuation, strict photoprotection and ongoing surveillance are indicated given the recently proposed premalignant potential of dermatomyositis-like eruptions and the aggressive nature of hydroxyurea-induced nonmelanoma skin cancer.

A patient treated for 4 months with hydroxycarbamide (hydroxyurea) for chronic myelomonocytic leukemia was admitted to hospital for recently developed severe dyspnea and acute respiratory failure. The computed tomographic scan of the chest showed diffuse ground glass opacities, some centrilobular low-density nodules (resembling hypersensitivity pneumonitis-like pattern), and minimal interstitial reticulation of the subpleural region. The analysis of bronchoalveolar lavage fluid excluded infection, as did serological examinations. The patient was started on oxygen therapy and with relief of thrombocytopenia and suspected hemolytic anemia, hydroxyurea treatment was discontinued. The patient underwent steroid therapy, with a rapid progressive improvement of clinical and radiological features. As hydroxyurea is increasingly used for a number of systemic disorders, physicians must be aware of its potential lung toxicity, requiring immediate cessation of the treatment and empiric corticosteroid therapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Chronic blood transfusion remains the most feasible therapeutic option for lifelong transfusion-dependent β-thalassemia (lifelong TDβT). However, it is associated with serious risks and complications. Hydroxyurea (HU), an oral chemotherapeutic drug, is expected to increase hemoglobin levels, thereby minimizing the burden of blood transfusion and its complications. Growing literature over the last twenty years suggests promising results of the use HU in lifelong TDβT; however, its role and safety remain unanswered questions. The objective of this study was to evaluate the clinical efficacy and safety of HU in patients with lifelong TDβT., Methods: MEDLINE, EMBASE, Cochrane databases, and major preceding conferences for studies that assessed HU in lifelong TDβT patients were searched. The effect size was estimated as a proportion (responder/sample size)., Results: Eleven observational studies, collectively involving 859 patients, fulfilled eligibility criteria. HU was associated with a significant decrease in transfusion need with complete and overall (≥50%) response rates of 26% [95% confidence interval (CI), 13-41%] and 60% (95% CI, 41-78%), respectively. No serious adverse effects were reported. All of the studies had several limitations, such as lack of a comparison group., Conclusion: HU appears to be effective, well tolerated; however, large randomized clinical trials should be done to confirm such findings.

The use of hydroxyurea (HU) as first line therapy in polycythemia vera (PV) has been criticized because no solid demonstration that this drug prevents thrombosis or prolongs survival has been so far produced. Here we present the outcomes of a large cohort of patients with PV included in the European Collaborative Low-dose Aspirin (ECLAP) study. We selected 1,042 patients who, during the follow-up, had received only phlebotomy (PHL) or HU to maintain the hematocrit level < 45%. To assure comparability, we conducted a propensity score matching analysis. The two groups (PHL n = 342 and HU n = 681) were well balanced for the parameters included in the propensity score (overall balance: χ 2  = 2.44, P = 0.964). Over a comparable period of follow-up (PHL = 29.9 vs. HU = 34.7 months), we documented an advantage of HU over PHL consistently significant with respect to the incidence of fatal/non-fatal cardiovascular (CV) events (5.8 vs. 3.0 per 100 person-years in PHL vs. HU group, P = 0.002) and myelofibrosis transformation that was only experienced by patients of PHL group. Evolution to acute leukemia was registered in three patients (two in PHL and one in HU group). The excess of mortality and total CV events in the PHL patients was restricted to the high-risk group, and, compared with HU cases, was significant higher in the PHL patients who failed to reach the hematocrit target < 0.45% (P = 0.000). In conclusion, this analysis provides reliable and qualified estimates of the therapeutic profile of HU and PHL treatments for future experimental studies and for the management of PV in clinical practice., (© 2017 Wiley Periodicals, Inc.)

Introduction: Sickle cell disease (SCD) represents one of the most common monogenic blood disorders worldwide, with an incidence of over 300,000 newborns affected per year. Reproductive challenges for men and women with SCD have been previously reviewed; however, evidence-based strategies to prevent and manage infertility and increase fecundity are lacking in women with SCD, which is one of the most important factors for quality of life. Areas covered: This review article summarizes the known risk factors for infertility, low fecundity, and premature menopause related to SCD. Expert commentary: Women with SCD have unique risk factors that may impact their ability to conceive, including chronic inflammation, oxidative stress, transfusion-related hemochromatosis, and ovarian sickling, causing ischemia and reperfusion injury to the ovary. Contraception is strongly recommended while on hydroxyurea therapy during reproductive years and discontinuing hydroxyurea for family planning and during pregnancy based on teratogenicity in animal studies. Hematopoietic stem cell transplantation (HSCT), the only curative therapy, sometimes involves conditioning regimens containing alkylating agents and total body irradiation that contribute to infertility and premature ovarian failure. Prior to HSCT or gene therapy, we strongly recommend referral to a reproductive endocrinologist to discuss fertility preservation and surrogacy options for all women with SCD.

Hydroxyurea is the primary pharmacotherapy to prevent complications of sickle cell anemia (SCA). Accumulated clinical experience across multiple age ranges has suggested that the use of an individualized maximum tolerated dose (MTD) will achieve optimal benefit of hydroxyurea treatment. However, the current empirical and trial-and-error approach for dose escalation often results in a lengthy titration process and is not strictly implemented in many clinics. Opportunities exist for pharmacokinetics model-based precision dosing of hydroxyurea to quickly achieve individual MTD. This review intends to introduce the use of a quantitative modeling approach including a Bayesian adaptive control strategy for the precision dosing of hydroxyurea. The rationale and practical considerations for the implementation of this approach are discussed. Future research directions with a focus on integrating specific safety and other clinical outcome endpoints into dose selection decision making are also discussed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Twenty-nail transverse melanonychia from hydroxyurea is a rare phenomenon, only reported four times previously. Here we describe a 51-year-old female who presented with 20-nail transverse melanonychia 3 months after initiating hydroxyurea therapy. Transverse melanonychia is a benign process but can cause patients significant distress, and thus is an entity with which dermatologists should recognize. We then review the cutaneous manifestations, differential diagnosis, and clinical considerations when evaluating patients with transverse melanonychia from hydroxyurea or other causes.

J Drugs Dermatol. 2017;16(8):814-815.

The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence-based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non-imaging TCD measurements (≥200 cm/s) received moderate fixed-dose hydroxyurea therapy (∼20 mg/kg/day). A comparison group of children with TCD measurements <200 cm/s was followed prospectively. Approximately 88% (330 of 375) of families agreed to be screened, while 87% (29 of 33) of those with abnormal TCD measurements, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85.7 fl at baseline to 95.5 fl at 24 months (not all of the children who crossed over had a 24 month visit), demonstrating adherence to hydroxyurea. The comparison group consisted of initially 210 children, of which four developed abnormal TCD measurements, and were started on hydroxyurea. None of the monthly research visits were missed (n = total 603 visits). Two and 10 deaths occurred in the treatment and comparison groups, with mortality rates of 2.69 and 1.81 per 100 patient-years, respectively (P = .67). Our results provide strong evidence, for high family recruitment, retention, and adherence rates, to undertake the first randomized controlled trial with hydroxyurea therapy for primary stroke prevention in children with SCA living in Africa., (© 2017 Wiley Periodicals, Inc.)

Background: Complications related to sickle cell disease (SCD) result in significant declines in health-related quality of life (HRQOL). While hydroxyurea reduces SCD complications, adherence remains suboptimal. The study's objectives were to assess the feasibility of Internet-based electronic assessment of HRQOL in SCD clinic and to examine the relationship between HRQOL and hydroxyurea adherence in adolescents and young adults (AYAs) with SCD., Procedure: A cross-sectional survey was administered on tablets to 34 AYAs (12-22 years old) in a SCD clinic from January through December 2015. Study measures included Patient Reported Outcomes Measurement Information System (PROMIS ® ) computerized adaptive testing and ©Modified Morisky Adherence Scale 8-items (©MMAS-8)., Results: Participants (59% male, 91% Black) had median age of 13.5 (range 12-18) years. Ninety-one percent completed PROMIS® measures electronically in the clinic, meeting our feasibility criterion of ≥85% completion rate. ©MMAS-8 scores positively correlated with fetal hemoglobin (HbF) (r s = 0.34, P = 0.04) and mean corpuscular volume (MCV) (r s = 0.42, P = 0.01) and inversely correlated with fatigue (r s = -0.45, P = 0.01), depression (r s = -0.3, P = 0.08), and social isolation (r s = -0.78, P = 0.02). Low ©MMAS-8 scores, indicating poor adherence, were associated with worse fatigue (P = 0.001) and trended toward significance for pain (P = 0.07) and depression (P = 0.06). Homozygous hemoglobin S disease patients with low HbF (<16%) had worse social isolation (P = 0.04) and those with low MCV (<102 fl) reported worse fatigue (P = 0.001), pain (P = 0.01), mobility (P = 0.01), and social isolation (P = 0.04)., Conclusions: HRQOL assessment in the SCD clinic is feasible. SCD patients with low hydroxyurea adherence and/or low HbF or MCV levels had worse HRQOL scores, particularly fatigue. Future prospective studies examining the relationship between HRQOL and hydroxyurea adherence are warranted., (© 2016 Wiley Periodicals, Inc.)

Introduction: Male Sickle cell disease (SCD) patients often have moderate to severe hypogonadism resulting in abnormal seminal fluid parameters due to testicular dysfunction. Hydroxyurea (HU), the only drug found to be effective in preventing morbidity and mortality in sickle cell disease patients has been found to further aggravate the testicular dysfunction., Material and Methods: This was a prospective study done at a tertiary care hospital over 26 months between September 2011 to October 2013. 100 male sickle cell disease patients of age group 15 to 45 years were recruited in the study. We evaluated seminal fluid indices in all patients and the effect of hydroxyurea on seminal fluid parameters. Hydroxyurea was given at low dose of 10mg/kg/day orally to patients with frequent vaso-occlusive crisis and frequent need of blood transfusion. Seminal fluid analysis was done according to WHO criteria before starting hydroxyurea and every 3 months after initiation of hydroxyurea. Patients with abnormal seminal parameters before hydroxyurea therapy were not given hydroxyurea therapy. Patients with abnormal sperm parameters were subjected for FNAC of testis. In sickle cell disease patients with hydroxyurea therapy, who developed abnormal seminal fluid parameters, hydroxyurea was stopped for 3 months and seminal fluid parameters were re-evaluated. Patients who had recovery of seminal indices after hydroxyurea cessation were restarted with hydroxyurea therapy at low dose., Results: Among Sickle cell disease patients without hydroxyurea therapy, 18% of patients developed oligospermia and 4% developed azoospermia. Among sickle cell disease patients with hydroxyurea therapy, 20% of patients developed oligospermia and 10% developed azoospermia. Seminal fluid parameters reverted back to normal after stoppage of hydroxyurea for 3 months in 73% of patients., Conclusions: Alteration of sperm parameters is seen in a significant number of sickle cell disease patients. Also, alterations of seminal fluid parameters are exacerbated by hydroxyurea treatment even with low dose. Therefore, treatment with hydroxyurea in adolescent and adult male sickle cell disease patients should be preceded by routine assessment of seminal fluid parameters and followed up regularly every 3 months for any change in seminal fluid parameters for evidence of hydroxyurea toxicity.

Background: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient., Objectives: To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD., Search Methods: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 19 September 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 06 October 2016., Selection Criteria: Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status., Data Collection and Analysis: We used standard Cochrane methodological procedures., Main Results: We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention.Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents).The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence).No deaths were reported in either trial.Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence).Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial)Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence).We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence).The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial)We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial)We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence).Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence).Neither trial reported on quality of life or cognitive function., Authors' Conclusions: We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD.Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises).In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions.Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention.All other evidence in this review is of very low-quality.

Background: Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising fetal haemoglobin. This is an update of a previously published Cochrane Review., Objectives: To assess the effects of hydroxyurea therapy in people with SCD (all genotypes), of any age, regardless of setting., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries.Date of the most recent search: 16 January 2017., Selection Criteria: Randomised and quasi-randomised controlled trials, of one month or longer, comparing hydroxyurea with placebo, standard therapy or other interventions for people with SCD., Data Collection and Analysis: Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias., Main Results: Seventeen studies were identified in the searches; eight randomised controlled trials were included, recruiting 899 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months.Four studies (577 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; three recruited individuals with only severe disease and one recruited individuals with all disease severities. There were statistically significant improvements in terms of pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use), measures of fetal haemoglobin and neutrophil counts and fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. There were no consistent statistically significant differences in terms of quality of life and adverse events (including serious or life-threatening events). Seven deaths occurred during the studies, but the rates by treatment group were not statistically significantly different.Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) compared hydroxyurea and phlebotomy to transfusion and chelation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts, but more occurrences of acute chest syndrome and infections in the hydroxyurea and phlebotomy group. There were no consistent statistically significant differences in terms of pain alteration and adverse events (including serious or life-threatening events). Two deaths occurred during the studies (one in a the hydroxyurea treatment arm and one in the control arm), but the rates by treatment group were not statistically significantly different. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early.The quality of the evidence for the above two comparisons was judged as moderate to low as the studies contributing to these comparisons were mostly large and well designed (and at low risk of bias); however evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events and results are applicable only to individuals with HbSS and HbSβºthal genotypes.Of the remaining two studies, one (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts but no statistically significant differences in terms of adverse events (including serious or life-threatening events).The final study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea - there was statistically significant improvement in terms of measures of fetal haemoglobin, but no statistically significant differences in terms of adverse events (including serious or life-threatening events). No participants died in either of these studies and other outcomes relevant to the review were not reported.The quality of the evidence for the above two comparisons was judged to be very low due to the limited number of participants, the lack of statistical power (as both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes., Authors' Conclusions: There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly in preventing chronic complications of SCD, recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with HbSC genotype. Future studies should be designed to address such uncertainties.

Background: The clinical prospects of hydroxyurea therapy in the management of sickle cell disease (SCD) require evaluation in the Nigerian setting to develop indigenous guidelines. This survey examines the pattern of hydroxyurea therapy, its clinico-haematologic benefits and safety profile in Nigerian SCD subjects., Methods: A cross sectional pilot survey was carried out among 60 adult SCD subjects over 3 months. Data on clinical phenotypes, relevant haematological parameters and details of hydroxyurea therapy were obtained using a structured questionnaire through an interview process and case file review., Results: The median age was 30 years. Thirty-four (56.7%) of the subjects are aware of hydroxyurea therapy in SCD. Twenty-four (40%) SCD patients had previously used hydroxyurea. Only 4 subjects were fully compliant. Reasons for non-compliance included poor knowledge and lack of funds. In particular, hydroxyurea reduced leucocyte count and increased mean red cell volume (MCV) in compliant subjects., Conclusion: Hydroxyurea use is low among Nigerian SCD subjects despite its proven efficacy/clinical prospects in the developed nations. Large scale multicenter studies and clinical trials are needed to form a basis for developing standard local treatment protocol for its use.

Objective: Chronic wounds are a major cause of morbidity and mortality. Approximately 20% to 23% of nonhealing wounds that are refractory to vascular intervention have other causes, including vasculitis, pyoderma gangrenosum, and other autoimmune diseases. The purpose of this article was to review the literature across medical and surgical specialties with regard to refractory chronic wounds associated with vasculitis and autoimmune diseases and to delineate clinical outcomes of these wounds in response to vascular and other interventions., Methods: An electronic search encompassing MEDLINE, PubMed, Cochrane Library, and Scopus was completed using the following search terms: rheumatoid arthritis; systemic sclerosis; systemic lupus erythematosus; antineutrophil cytoplasmic antibody-associated vasculitis; mixed connective tissue disease; antiphospholipid syndrome; pyoderma gangrenosum; thromboangiitis obliterans; cryoglobulinemia; hydroxyurea; sickle cell; atrophie blanche; livedoid vasculitis; cholesterol emboli; calciphylaxis; antiphospholipid antibodies; prothrombotic; combined with the terms: chronic wound and leg ulcer. Full-text articles published in English up to March 1, 2016, that investigated the clinical outcomes of chronic wounds associated with autoimmune diseases were included. Review articles and evaluations of management of chronic wounds were also reviewed. Primary outcomes included in the review were amputation, ulcer healing, reduction in wound size, overall survival, and freedom from reintervention. Owing to the heterogeneity of data reporting among articles, qualitative analysis is also reported., Results: Vasculitis and autoimmune diseases play a role in 20% to 23% of patients with chronic lower extremity ulcers. Furthermore, patients with autoimmune disease have a significantly high rate of split thickness skin graft failure (50% compared to 97% in patients without autoimmune disease; P = .0002). The management of leg ulcers associated with autoimmune diseases is discussed., Conclusions: Autoimmune and vasculitic causes should be considered in patients with chronic wounds who do not respond to appropriate vascular intervention and standard local wound care. A multidisciplinary approach with the involvement of rheumatologists allows investigation for underlying systemic disease and improves clinical outcomes for many of these challenging patients., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Postnatal development of the cerebellar cortex was studied in rats administered with a single dose (2 mg/g) of the cytotoxic agent hydroxyurea (HU) on postnatal day (P) 9 and collected at appropriate times ranging from 6 h to 45 days. Quantification of several parameters such as the density of pyknotic, mitotic, BrdU-positive, and vimentin-stained cells revealed that HU compromises the survival of the external granular layer (EGL) cells. Moreover, vimentin immunocytochemistry revealed overexpression and thicker immunoreactive glial processes in HU-treated rats. On the other hand, we also show that HU leads to the activation of apoptotic cellular events, resulting in a substantial number of dying EGL cells, as revealed by TUNEL staining and at the electron microscope level. Additionally, we quantified several features of the cerebellar cortex of rats exposed to HU in early postnatal life and collected in adulthood. Data analysis indicated that the analyzed parameters were less pronounced in rats administered with this agent. Moreover, we observed several alterations in the cerebellar cortex cytoarchitecture of rats injected with HU. Anomalies included ectopic placement of Purkinje cells and abnormities in the dendritic arbor of these macroneurons. Ectopic granule cells were also found in the molecular layer. These findings provide a clue for investigating the mechanisms of HU-induced toxicity during the development of the central nervous system. Our results also suggest that it is essential to avoid underestimating the adverse effects of this hydroxylated analog of urea when administered during early postnatal life.

Stalling at DNA replication forks generates stretches of single-stranded (ss) DNA on both strands that are exposed to nucleolytic degradation, potentially compromising genome stability. One enzyme crucial for DNA replication fork repair and restart of stalled forks in human is Metnase (also known as SETMAR), a chimeric fusion protein consisting of a su(var)3-9, enhancer-of-zeste and trithorax (SET) histone methylase and transposase nuclease domain. We previously showed that Metnase possesses a unique fork cleavage activity necessary for its function in replication restart and that its SET domain is essential for recovery from hydroxyurea-induced DNA damage. However, its exact role in replication restart is unclear. In this study, we show that Metnase associates with exonuclease 1 (Exo1), a 5'-exonuclease crucial for 5'-end resection to mediate DNA processing at stalled forks. Metnase DNA cleavage activity was not required for Exo1 5'-exonuclease activity on the lagging strand daughter DNA, but its DNA binding activity mediated loading of Exo1 onto ssDNA overhangs. Metnase-induced enhancement of Exo1-mediated DNA strand resection required the presence of these overhangs but did not require Metnase's DNA cleavage activity. These results suggest that Metnase enhances Exo1-mediated exonuclease activity on the lagging strand DNA by facilitating Exo1 loading onto a single strand gap at the stalled replication fork., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Backround: Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation.This is an update of a Cochrane Review first published in 2002, and last updated in 2013., Objectives: To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts)., Search Methods: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 04 April 2016.We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 25 April 2016., Selection Criteria: Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status., Data Collection and Analysis: Two authors independently assessed trial eligibility and the risk of bias and extracted data., Main Results: We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease.Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents).The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates. Red cell transfusions versus standard care Children with no previous long-term transfusionsLong-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence.Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence.We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence. Children and adolescents with previous long-term transfusions (one trial, 79 participants)We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence.Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks).The trial did not report neurological impairment, or quality of life. Hydroxyurea and phlebotomy versus red cell transfusions and chelationNeither trial reported on neurological impairment, alloimmunisation, or quality of life. Primary prevention, children (one trial, 121 participants)Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease-related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence. Secondary prevention, children and adolescents (one trial, 133 participants)Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence., Authors' Conclusions: There is no evidence for managing adults, or children who do not have HbSS sickle cell disease.In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications.In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration.In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events.All other evidence in this review is of very low quality.

Hydroxyurea is a medication with many well-described cutaneous side effects, notably the dermatomyositis-like eruption known as hydroxyurea dermopathy. Although systemic lupus erythematosus has been reported with hydroxyurea use, cutaneous lupus has not. We report a novel case of chronic cutaneous lupus induced by hydroxyurea and propose that this is a side effect that is distinct from hydroxyurea dermopathy., (© 2016 Wiley Periodicals, Inc.)

In addition to main categories of medications believed to have negative impacts on male reproduction, there are a number of miscellaneous drugs with some evidence for such adverse reactions. Because of its widespread use and over-the-counter availability, the H 2 receptor antagonist cimetidine is most concerning. As a competitive antagonist at androgen receptors, it can impact the HPG axis and semen quality. In this chapter, we review the studies of this drug and other histamine H 2 receptor antagonists in men and experimental species. Several other medications are concerning and the evidence for negative effects on reproduction are covered: colchicine, domperidone, hydroxyurea, metformin, metoclopramide, mifepristone, retinoids, and statins.

Hydroxyurea (Hu) is widely used as first-line cytoreductive therapy for patients with high-risk Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPN), but a small proportion of patients have refractory disease or experience adverse effects. Studies have demonstrated busulfan (Bu) to be an active first-line agent, but data on its role as second-line or later therapy are minimal. To evaluate its efficacy and safety in this context, we undertook a multicenter audit of Ph-neg MPN patients who had received Bu as therapy for Hu intolerance or failure. Of 51 patients identified, 38 (75%) achieved either complete or partial hematological response following at least one Bu cycle. Bu was generally well tolerated, with only 21/135 (15%) cycles complicated by adverse effects, predominantly cytopenia; only 6% of cycles were ceased due to treatment complications. Bu is an effective and well-tolerated agent in patients with Ph-neg MPN in the setting of Hu intolerance or unresponsiveness.

Ambulatory care clinical pharmacy services have expanded beyond primary care settings, but literature supporting the benefits of clinical pharmacy involvement with patients who have rare diseases such as sickle cell disease (SCD) is lacking. Hydroxyurea is the only agent approved by the U.S. Food and Drug Administration for the treatment of SCD; full benefit in controlling pain episodes and other complications is achieved through monitored escalation to a maximum tolerated dose. The primary objective of this analysis was to evaluate the impact of a newly implemented clinical pharmacy service on the management of patients with SCD. We performed a retrospective cross-sectional analysis of 385 adults with SCD who received care between January 1, 2014, and December 31, 2014, at a single Sickle Cell Outpatient Center that implemented a clinical pharmacy service in August 2013. Data were collected on hydroxyurea dose escalation, immunization completion rates, and health maintenance metrics (screening for nephropathy with microalbuminuria testing, retinopathy with annual retinal examinations, and pulmonary hypertension with echocardiography). The impact of the clinical pharmacy service on quality measurements was evaluated by using univariate and multivariate analyses. The number of pharmacist encounters, defined as a clinic visit when a clinical pharmacist interacted with a patient as documented in the medical records, was associated with an improved hydroxyurea dose escalation rate (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.07-2.05, p=0.02). Immunization rates for the 23-valent pneumococcal polysaccharide vaccine, the 13-valent pneumococcal conjugate vaccine, and influenza vaccine were 66%, 47%, and 62%, respectively. The number of pharmacist encounters was associated with improved immunization completion rates (OR 1.38, 95% CI 1.17-1.62, p<0.001). Improved screening for microalbuminuria (OR 2.14, 95% CI 1.60-2.86, p<0.001) and sickle cell retinopathy (OR 1.16, 95% CI 1.00-1.35, p=0.05) were also associated with the number of pharmacist encounters. A new clinical pharmacy service implemented in managing a rare disease, SCD, was associated with an improved hydroxyurea dose escalation rate, immunization completion rates, and health maintenance metrics., (© 2016 Pharmacotherapy Publications, Inc.)

Sickle cell disease (SCD) pain transitions from acute to chronic for unknown reasons. Chronic elevation of the pain neurotransmitter substance P (SP) sensitizes pain nociceptors. We evaluated SP levels in controls and SCD patients during baseline and acute pain and investigated associations between SP and age, gender, pain history, haemolysis and hydroxycarbamide (also termed hydroxyurea) use. Plasma SP levels were measured using enzyme-linked immunosorbent assay. Independent samples t-test compared SP levels between: (i) SCD baseline and controls, and (ii) SCD baseline and acute pain. Multivariate linear regression determined associations between SP and age, gender, pain history and hydroxycarbamide use. Spearman correlation determined an association between SP and haemolysis. We enrolled 35 African American controls, 25 SCD baseline and 12 SCD pain patients. SCD patients were 7-19 years old. Mean ± standard deviation SP level (pg/ml) in SCD baseline was higher than controls (32·4 ± 11·6 vs. 22·9 ± 7·6, P = 0·0009). SP in SCD pain was higher than baseline (78·1 ± 43·4 vs. 32·4 ± 11·6, P = 0·004). Haemolysis correlated with increased SP: Hb (r = -0·7, P = 0·0002), reticulocyte count (r = 0·61, P = 0·0016), bilirubin (r = 0·68, P = 0·0216), lactate dehydrogenase (r = 0·62, P = 0·0332), aspartate aminotransferase (r = 0·68, P = 0·003). Patients taking hydroxycarbamide had increased SP (β = 29·2, P = 0·007). SP could be a mediator of or marker for pain sensitization in SCD and a biomarker and/or target for novel pain treatment., (© 2016 John Wiley & Sons Ltd.)

Sickle cell disease (SCD) is a blood disease caused by a single nucleotide substitution (T > A) in the beta globin gene on chromosome 11. The single point mutation (Glu6Val) promotes polymerization of hemoglobin S (HbS) and causes sickling of erythrocytes. Vaso-occlusive painful crises are associated with recurrent and long-term use of analgesics/opioids and hydroxyurea (HU) by people living with SCD. The present analysis offers a state-of-the-art expert review of the effectiveness of pharmacogenomics/genetics of pain management in SCD, with specific focus on HU and opioids. The literature search used the following keywords: SCD, pharmacogenomics, pharmacogenetics, pain, antalgics, opioids, morphine, and HU. The literature was scanned until March 2016, with specific inclusion of targeted landmark and background articles on SCD. Surprisingly, our review identified only a limited number of studies that addressed the genetic/genomic basis of variable responses to pain (e.g., variants in OPRM1, HMOX-1, GCH1, VEGFA COMT genes), and pharmacogenomics of antalgics and opioids (e.g., variants in OPRM1, STAT6, ABCB1, and COMT genes) in SCD. There has been greater progress made toward identifying the key genomic variants, mainly in BCL11A, HBS1L-MYB, or SAR1, which contribute to response to HU treatment. However, the complete picture on pharmacogenomic determinants of the above therapeutic phenotypes remains elusive. Strikingly, no study has been conducted in sub-Saharan Africa where majority of the patients with SCD live. This alerts the broader global life sciences community toward the existing disparities in optimal and ethical targeting of research and innovation investments for SCD specifically and precision medicine and pharmacology research broadly., Competing Interests: Author Disclosure Statement The authors declare that no conflicting financial interests exist.

Sickle cell disease (SCD) is an inherited disorder in which sickled red blood cells occlude the small vessels of the body, reducing oxygen delivery to tissues and ultimately negatively affecting many of the body's major organs. Hydroxyurea has proven beneficial in the treatment of SCD and prevention of disease-related complications. The 2014 guidelines put forth by the National Heart, Lung, and Blood Institute recommend hydroxyurea treatment in infants 9 months and older, children, and adolescents with SCD-SS or SCD-Sβ(0) thalassemia regardless of clinical severity. This is a change from the 2002 guidelines in which hydroxyurea was recommended for adolescents and children with SCD-SS or SCD-Sβ(0) thalassemia with frequent episodes of pain, a history of acute chest syndrome, severe and symptomatic anemia or other severe vaso-occlusive events. Nurses play a critical role in working with patients and families to provide education, guidance, and support to improve compliance to mitigate the long-term effects of SCD., (© 2015 by Association of Pediatric Hematology/Oncology Nurses.)

Background: 'Hydroxyurea-induced Squamous Dysplasia' (HISD) is a cutaneous side-effect related to chronic oral treatment with Hydroxyurea. Ingenol mebutate gel is a topical drug approved for the treatment of multiple, non-hypertrophic actinic keratoses (AK) localized within a limited cancerization field. Since HISD may be considered as a drug-induced variant of classic AK, ingenol mebutate is likely to have therapeutic effects., Objectives: The aim of this study was to evaluate efficacy and safety of ingenol mebutate 150 mcg/g and 500 mcg/g, as a treatment of HISD lesions on face/scalp and trunk/extremities respectively., Methods: Seven areas with a mean of lesions of 5.9 ± 1.7 in five patients with HISD were treated. Patients with lesions on face/scalp self-treated a 25 cm(2) skin affected area with ingenol mebutate gel 150 mcg/g, one tube daily for 3 days. Patients with lesions localized on trunk/extremities treated the same size affected area with ingenol mebutate gel 500 mcg/g, one tube daily for 2 days. Clinical assessment and count of HISD lesions has been performed by an experienced dermatologist at day 0, at day 57, and at time of last feasible follow-up visit (median 337 days). Safety assessment included the report of all SAEs., Results: At 57-day follow-up, we observed an overall response rate (ORR) - the sum of Complete Responses (CR) + Partial Responses (PR) - of 87.5%, with a 57.1% CR, and a 78.0% total lesions' reduction compared to time 0 (P < 0.01). On a median follow-up of 337 days, we observed a long-term ORR of 71.4%, a 57.1% CR ratio and a 65.9% total lesions' reduction compared to time 0 (P = 0.01). No severe (grade 3-4) adverse events have been reported., Conclusion: Although obtained in a small case series, these encouraging data lead us to propose ingenol mebutate gel as a possible treatment for HISD., (© 2016 European Academy of Dermatology and Venereology.)

Hydroxyurea is an excellent therapeutic agent for the pharmacological induction of HbF in patients with sickle cell disease (SCD). However, all completed clinical trials of hydroxyurea have excluded patients with hemoglobin SC (HbSC) disease. HbSC differs significantly in pathophysiology from HbSS, as HbC does not sickle, but instead causes cellular dehydration which potentiates sickling of HbS. Many severely affected HbSC patients have been placed on hydroxyurea on a case by case basis, but there are no large scale prospective data on safety or efficacy of hydroxyurea in this subset of patients with SCD. Here, we report a case series of 14 pediatric patients with HbSC treated to maximum tolerated dose (MTD) with hydroxyurea. Those who failed to show clinical improvement after at least six months at MTD were offered phlebotomy in addition to hydroxyurea. Five out of 11 patients with HbSC who achieved MTD failed to demonstrate clinical improvement on hydroxyurea. Of the four placed on dual hydroxyurea and phlebotomy therapy, all showed at least partial clinical improvement. Percent dense red blood cells (%DRBC) were measured via an ADVIA hematology analyzer. A marked rise in percent dense cells preceded clinical complications in three patients. Dual therapy with hydroxyurea and phlebotomy may be an effective approach to patients with HbSC that do not experience improvement with hydroxyurea alone. Monitoring of %DRBC may predict adverse events and aid in assessing hydroxyurea compliance. Large scale clinical trials are needed to evaluate the safety and efficacy of hydroxyurea and hydroxyurea with phlebotomy in patients with HbSC disease., (© 2016 by the Society for Experimental Biology and Medicine.)

Unlabelled: The goals of therapy in patients with polycythemia vera (PV) are to improve disease-related symptoms, prevent the incidence or recurrence of thrombosis, and possibly delay or prevent the transformation into myelofibrosis or acute myeloid leukemia (AML). Cytoreductive therapies have been used in older patients and those with a history of thrombosis to achieve these goals. Hydroxyurea (HU) remains the first-line cytoreductive choice; however, up to one in four patients treated with HU over time will develop resistance or intolerance to HU. More importantly, patients who fail HU have a 5.6-fold increase in mortality and a 6.8-fold increase risk of transformation to myelofibrosis or AML; therefore, alternative therapies are needed for these patients. Interferon-α has been used in PV and has shown significant activity in achieving hematologic responses and decreasing JAK2 V617F mutation allele burden. JAK inhibition has also been investigated and recently garnered regulatory approval for this indication. In this review, we will discuss the current treatment options that are available for patients after HU and the novel therapies that are currently under investigation., Implications for Practice: The outcomes of PV patients who fail or who are intolerant of hydroxyurea are poor. Although pegylated interferon can be considered in younger patients, currently, ruxolitinib is the only U.S. Food and Drug Administration-approved agent in this setting, representing a viable option, leading to hematocrit control and a reduction in spleen size and constitutional symptoms. Although a small number of patients will achieve a molecular response with continuous treatment, the implications of such response on the clinical outcomes are still unknown. Patients whose disease is not adequately controlled with ruxolitinib, or who lose their response, can be treated with low-dose busulfan or pipobroman; however, they should be encouraged to participate in trials with novel therapies., (©AlphaMed Press.)

Patients with Non-Transfusion-Dependent Thalassemia may require regular transfusion therapy. However, these patients are at risk of developing irregular antibodies, making them untransfusable. Second line treatment usually includes hydroxyurea, which however is not effective in all patients. Other treatment options include thalidomide, which has been reported to be safe and effective in selected patients. We report the case of a patient who experienced improvement of hemoglobin levels and of a part of NTDT related complications, following 36months of continuous therapy with low doses of thalidomide., (Copyright © 2016 Elsevier Inc. All rights reserved.)