An Extension Study of IMR-687 in Adult Patients With Sickle Cell Anemia

Abstract Sickle cell anemia (SCA) may cause a variety of neurological complications, including stroke and headaches. Stroke occurs in up to 9% of children with SCA, and transcranial Doppler (TCD) studies have demonstrated that increased velocities are related to higher stroke risk. Throbbing headache occurs in SCA but its cause, frequency, and relationship to TCD velocities have received little attention. On the other hand, there are few TCD studies in adult patients. Our aims were: 1) to describe the main features of TCD in adult SCA patients, and 2) to investigate if there were correlation between TCD features and presence of headache. TCD was performed in 56 adult SCA patients (≥ 16 years old) and in 56 healthy individuals (HI), matched by age and race. There were 6 patients with a remote history of stroke but none were on chronic transfusion. The SCA group was submitted to a neurological evaluation and specifically asked about the occurrence of headache and its characteristics. The highest flow velocity (maxFV) recorded for each artery was considered the most representative. We analyzed the frequency of FV asymmetry (side-to-side difference > 20%) and focal FV changes. The mean maxFV was significantly higher in patients (117.7 ± 21.6 cm/s) than in HI (72.45 ± 11.48 cm/s) (p<0.005). Only one patient had maxFV higher than 170 cm/s. The frequencies of asymmetry and of focal FV changes were significantly higher in SCA. Forty-one patients (73.2%) reported having headaches. Twenty-eight patients (50%) had severe (= 5 for pain intensity at a 1–10 scale) and frequent headaches (at least once a month). This group of patients presented TCD velocities significantly higher than patients without or with milder headaches (p=0.035). In conclusion, TCD maxFV was significantly higher in adult patients with SCA than HI, however, only one patient was considered at risk of stroke according to TCD criteria described in children. FV asymmetry and focal FV changes may be markers for arterial disease in adult SCA patients, and need to be further confirmed by neuroimaging and clinical follow up studies. The patients with severe headaches presented TCD velocities significantly higher than patients without or with milder headaches, but this finding needs to be confirmed by more and larger studies.

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Definition of the Responder to Hydroxyurea Therapy: Revisited.

Blood ◽

10.1182/blood.v114.22.1513.1513 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1513-1513 ◽

Cited By ~ 1

Author(s):

Samir K. Ballas ◽

William F. McCarthy ◽

Robert L Bauserman ◽

Faramarz Valafar ◽

Myron Waclawiw ◽

...

Keyword(s):

Placebo Group ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Adult Patients ◽

Study Endpoint ◽

Primary Study ◽

Analgesic Use ◽

Daily Pain ◽

At Home

Abstract Abstract 1513 Poster Board I-536 Introduction Treatment of sickle cell anemia with hydroxyurea (HU) is associated with significant decreases in the frequency of painful crises, acute chest syndrome, morbidity, and mortality. Some patients, however, show no improvement even with prolonged HU therapy. Identifying treatment responders is important for predicting clinical improvements and for assessing the risk/benefit ratio of HU treatment for individual patients. The salutary effects of HU are thought to be the result of increasing the fetal hemoglobin (Hb F) level. NHLBI guidelines for sickle cell treatment define levels of 15%-20% Hb F as therapeutic endpoints. Research and reviews based on pediatric and adult patients have variously argued that levels from about 10% to 20% are beneficial. Patients and Methods Patients in this study were from the Multicenter Study of Hydroxyurea (MSH) in Sickle Cell Anemia, a randomized double-blind placebo controlled trial of HU. The N=299 adult patients were recruited from 21 sites across the U.S. and Canada, and were evenly distributed between males and females. Following randomization to placebo or HU, patients had biweekly follow-up visits until the trial was terminated early due to a significant reduction in painful crises (the primary study endpoint) in the HU arm. Levels of Hb F in MSH patients were assessed at baseline and again approximately 18-21 months after treatment began, with the level at each time being the average of two measurements. In the previously reported MSH study, patients were divided into quartiles of Hb F change as a measure of response to HU treatment. In this approach the bottom two quartiles showed either no or minimal positive change in Hb F levels, and fully overlapped with placebo group in the extent of change. We redefined HU patients as ‘responders’ or ‘nonresponders’ based on a 15% Hb F threshold; those with baseline HbF below 15% and follow-up above 15% were labeled ‘responders,’ while all others were labeled ‘nonresponders.’ The 15% level was chosen due to its frequent identification in previous publications as a level at which meaningful benefits could be expected. For both coding schemes, we compared the following outcomes between subgroups: rate of painful crises, proportion of days at home with pain and with opioid use, and average daily pain. Results Using the 15% rule, responders had significantly better outcomes than nonresponders on all outcome measures: rate of painful crises (p=.011), proportion of at-home days with pain (p=.025), proportion of days with analgesic use (p=.002), and average daily pain (p<.0001). Nonresponders, in turn, did not differ from the placebo group on any of these outcomes. Using the quartiles approach, the highest quartile had significantly fewer painful crises (p<.05) than the bottom two and placebo, but did not differ from the second highest; for the proportion of days with pain, the highest group did not differ from 2 of the other 3 quartiles or from the placebo group. Only for proportion of days with analgesic use and average daily pain did the highest quartile significantly differ from all other quartiles and from placebo patients. Finally, applying the 15% rule to the pl‘cebo group resulted in no placebo patients being mislabeled as treatment responders, suggesting that increases above the 15% cutoff for post-treatment Hb F levels is outside normal variability in sickle cell patients not in HU treatment. Conclusions The 15% Hb F rule successfully identified a ‘responder’ group that significantly differed from other HU patients and from placebo patients on all outcomes, including painful crises. Despite overlap with responders under the 15% rule, patients in the highest quartile for Hb F change did not consistently differ from all other quartiles or placebo on the primary outcome (painful crises) and on proportion of days with pain. Our data suggest that using the 15% Hb F threshold identifies a subset of patients with the best clinical outcomes. Disclosures No relevant conflicts of interest to declare.

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Hydroxyurea Shows Clinical Benefit without Alteration of Fetal Hemoglobin, MCV, or Hemoglobin in Unselected Adult and Pediatric Patients with Sickle Cell Anemia

Blood ◽

10.1182/blood.v126.23.2187.2187 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2187-2187

Author(s):

Crawford John Strunk ◽

Biree Andemariam ◽

Fredericka Sey ◽

Fatimah Farooq ◽

Rebekah Urbonya ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Multicenter Study ◽

Pediatric Patients ◽

Laboratory Data ◽

Fetal Hemoglobin ◽

Adult Patients ◽

Clinical Severity ◽

Laboratory Studies ◽

Laboratory Values

Abstract Introduction Sickle cell anemia is the most common single gene defect in the United States, affecting approximately 100,000 individuals (Hassel Am J Prev Med 2010). It is characterized by chronic hemolysis, unpredictable vaso-occlusive episodes (VOEs), and chronic organ damage leading to early death in patients affected by the disorder. Hydroxyurea, a small molecule chemotherapeutic agent, has been used to treat patients with severe sickle cell disease since 1984 (Brawley Ann Intern Med 2008). Two randomized controlled trials, the Multicenter Study of Hydroxyurea (Charache N Engl J Med 1995) in adults and the Baby HUG trial (Wang Lancet 2011) in children, showed that hydroxyurea reduced the number of VOEs and hospital admissions, while simultaneously increasing hemoglobin and fetal hemoglobin in patients with sickle cell anemia. The goal of this study was to determine the clinical effectiveness of hydroxyurea in reducing the number VOEs and hospitalizations in unselected patients with sickle cell anemia. Methods The CASIRE group is an international multi-institutional collaborative group evaluating the clinical severity of patients with sickle cell anemia through a validated questionnaire, chart review and laboratory studies. Patients were enrolled on the CASIRE study after informed consent and assent was obtained from either the parent or patient when appropriate. The study was approved at each participating institution's IRB. A questionnaire was answered by the parents and/or patient, and baseline and current laboratory studies were collected. Patients were stratified into those who were not on hydroxyurea, and those who were currently on hydroxyurea. Number of VOEs, admissions, baseline and current fetal hemoglobin, and change in hemoglobin and MCV were compared. Results There were 349 patients in this study (134 on hydroxyurea). Baseline laboratory data are reported in table 1. Hemoglobin level and MCV were not statistically different in patients prior to and after taking hydroxyurea (table 2). Fetal hemoglobin in adults increased 2.7 times baseline, whereas in children it was unchanged. All patients on hydroxyurea had a reduction of VOEs, ED visits and admissions compared to prior to hydroxyurea (see table 3). Table 1. Baseline laboratory data Baseline data Patients on Hydroxyurea Patients not on Hydroxyurea Pediatric Adult Pediatric Adult N 78 56 140 75 Age 10 26.9 8.6 28.3 Hemoglobin (g/dL) 8.7 9.7 9.39 9.4 MCV (fL) 91 91.5 79 86 Fetal Hemoglobin (%) 15.1 12.4 9.6 5 Table 2. Clinical data for patients on HU Patients on Hydroxyurea Pediatric (78) Adult (56) Dose of HU (mg/kg) 23.8 20.5 # doses missed/wk 1 1.55 Fetal Hemoglobin on HU (%) 14.5 13.8 D MCV from baseline (fL) +5.4 +0.1 D Hgb from baseline (g/dL) +0.23 +0.4 Table 3. Number of pain episodes in patients on HU. Prior to HU In last year on HU 2 tailed paired t test Pediatric patients (N = 78) # pain episodes/year 25 12.9 0.62 # requiring ED/year 2.66 1 0.93 # requiring admission/year 4.28 1.79 0.017 Adult patients (N = 56) # pain episodes/year 36.7 28.6 0.021 # requiring ED/year 5.7 2.4 0 # requiring admission/year 6.6 3.15 0.117 Conclusion The Multicenter Study of Hydroxyurea and the BABY HUG study showed that hydroxyurea is efficacious for patients with sickle cell anemia. No previous study has evaluated the effectiveness of hydroxyurea in clinical practice. Our study suggests that, although baseline and current laboratory values are similar in patients prior to versus after taking hydroxyurea, there was a clear reduction in the number of VOEs and admissions, similar to the Baby HUG and MSH studies. These results suggest that the reduction of VOEs could be the product of a generalized decrease in overall inflammation and hemolysis or increased nitric oxide production rather than an increase in fetal hemoglobin by itself. Reasons for the similarity in laboratory values could include the length of time patients have been on hydroxyurea or that hydroxyurea was not escalated to maximum tolerated dose. Another reason may be the degree of compliance of patients in a clinical setting. We noted that 1/3 of our pediatric and ½ of our adult patients missed at least 1 dose of hydroxyurea per week suggesting that even partial compliance with hydroxyurea may prove beneficial clinically. This study demonstrates that hydroxyurea is effective in reducing the number of VOEs and admissions for unselected patients with sickle cell anemia. Disclosures No relevant conflicts of interest to declare.

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Serum Ionized Magnesium Levels and Ionized Calcium to Magnesium Ratios in Adult Patients with Sickle Cell Anemia

Academic Emergency Medicine ◽

10.1197/j.aem.2004.02.151 ◽

2004 ◽

Vol 11 (5) ◽

pp. 548-548

Author(s):

S. Zehtabchi

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Adult Patients ◽

Ionized Calcium ◽

Ionized Magnesium

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STUDIES ON CONGENITAL HEMOLYTIC SYNDROMES

PEDIATRICS ◽

10.1542/peds.23.3.462 ◽

1959 ◽

Vol 23 (3) ◽

pp. 462-475

Author(s):

Marion E. Erlandson ◽

Irving Schulman ◽

Carl H. Smith

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Pediatric Patients ◽

Clinical Manifestations ◽

Adult Patients ◽

Present Series ◽

Risk Of Infection ◽

Laboratory Examination ◽

Careful Observation ◽

Compensation Index

Four adult patients were studied in whom classic congenital spherocytic anemia was evident clinically and by laboratory examination. Anemia, as determined by total volume of erythrocytes, was marked although concentrations of hemoglobin were only slightly low. Rates of destruction and production of erythrocytes were markedly accelerated. Six pediatric patients with minimal clinical manifestations but definite laboratory evidence of congenital spherocytosis were evaluated. Anemia, in terms of total volume of erythrocytes, was present in all patients despite normal concentrations of hemoglobin in some patients. A potential for future severe clinical manifestations was shown to be present in five of six children by the demonstration of marked hemolytic defects equivalent to the hemolytic defects present in adult patients with classic congenital spherocytic anemia. In the present series of patients with congenital spherocytosis in whom concentrations of hemoglobin were normal or slightly low, values for the total volume of erythrocytes and the compensation index were similar to values in patients with intermediate (homozygous) thalassemia and in many patients with sickle cell anemia. Abnormally low values for total volume of erythrocytes and compensation index were present in four patients in whom the rate of destruction of erythrocytes was less than six times normal. Rates of production of erythrocytes were less than six times normal in the majority of patients studied. This is contrary to a previous concept of the capacity for erythropoietic compensation in such patients. These values imply that some factor(s) which has not as yet been identified regulates the rate of erythropoiesis in these patients. Studies of four family groups of patients with congenital spherocytosis demonstrated the absence of any specific familial pattern of manifestations of the disease. It has been suggested that management of children with minimal symptoms resulting from the presence of this disease consists of careful observation, splenectomy being deferred until late in childhood to avoid a maximal risk of infection after splenectomy. It has also been suggested that splenectomy be performed before the age of 10 years in order to avoid the complication of gallstones, and that splenectomy be performed at an even earlier age if persistent severe symptoms are present. The existence of a truly mild hemolytic defect was demonstrated in only 1 of the 10 patients studied. It would seem that splenectomy is not indicated in this unusual patient.

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Exchange Transfusion In Adult Patients With Sickle Cell Disease With Refractory Vaso-Occlusive Crises

Blood ◽

10.1182/blood.v122.21.4689.4689 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4689-4689 ◽

Cited By ~ 1

Author(s):

Padmini Moffett ◽

Bryan K Moffett

Keyword(s):

African American ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Exchange Transfusion ◽

Iron Chelation ◽

Adult Patients ◽

Cell Disease ◽

Psychological Burden ◽

Ed Visits

Sickle cell disease occurs in 1/500 African-American births. Pain is one of the most common complications of sickle cell disease and is associated with depression, anxiety, decreased quality of life and poor sleep patterns. Vaso-occlusive crises resulting in three or more hospitalizations per year occur in 48% of patients with sickle cell disease (Annals of Emergency Medicine - May 2009 (Vol. 53, Issue 5, Pages 587-593). Hydroxyurea has been shown to ameliorate the frequency of painful vaso-occlusive crises in sickle cell anemia (Charache et al, Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia NEJM. 1995), unfortunately many eligible patients are not treated due to psychosocial reasons and fear of teratogenicity or malignancy or have painful crisis refractory to hydroxyurea. A panel of experts has suggested that RBC exchange transfusion in these patients may decrease ED visits and subsequent hospitalizations based on anecdotal evidence [Best practices for transfusion for pateitns with sickle cell disease. T Wun, K Hagel. Hematology Review 2009, July 1; 1(22); e22]. We present the case of a 31 year old African-American male with Hgb S/beta thalassemia + with complications of sickle cell disease including Parvovirus B19 induced aplastic anemia, iron overload secondary to multiple simple transfusions, multiple vaso-occlusive crises as well as a left lower extremity ulcer precipitated by treatment with hydroxyurea. He was treated with folic acid as well as deferasirox for iron chelation. He began PRBC exchange transfusions every 6 weeks in March of 2011. In the one year prior to exchange transfusion initiation he had 13 ED visits and 4 hospitalizations for vaso-occlusive crises. After initiation of exchange transfusions he had 11 ED visits and 2 hospitalizations for vaso-occlusive crises the following year. An elevated WBC is associated with poor outcomes in sickle cell disease (Miller et al Predictors of adverse outcomes in children with sickle cell disease. N Engl J Med 2000). His average WBC level was 13 x 109/L, which decreased to 11 x 109/L after initiation of exchange transfusion. The patient underwent extended typing for E,C, and Kell RBC antigens to minimize development of antibodies. Though monthly exchange transfusions are costly and carry the attendant risk of antibody formation, this may be offset by reducing the financial and psychological burden of frequent hospitalizations for management of refractory vaso-occlusive crises. Exchange transfusion may also ameliorate the cost associated with long-term iron chelation. Further investigation is warranted to determine whether a program of monthly exchange transfusions can curtail ED visits and hospitalizations in adult patients with sickle cell disease and multiple, refractory vaso-occlusive crises. Disclosures: No relevant conflicts of interest to declare.

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