Clark Brown

Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities

Chronic transfusions are recommended for children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities ( 200 cm/sec) to help prevent the occurrence of a primary stroke [1]. The goal is usually to maintain the sickle hemoglobin concentration (HbS) <30%; however, this goal is often difficult to achieve in clinical practice. The NHLBI-sponsored trial ‘‘TCD With Transfusions Changing to Hydroxyurea (TWiTCH)’’ will compare standard therapy (transfusions) to alternative therapy (hydroxyurea) for the reduction of primary stroke risk in this patient population. Transfusions will be given according to current transfusion practices at participating sites. To determine current academic community standards for primary stroke prophylaxis in children with SCA, 32 clinical sites collected data on 340 children with abnormal TCD velocities receiving chronic transfusions to help prevent primary stroke. The average (mean ± 1 SD) pretransfusion HbS was 34 ± 11% (institutional average 23–48%); the 75th and 90th percentiles were 41 and 50%, respectively. Lower %HbS was associated with higher pretransfusion Hb values and receiving transfusions on time. These data indicate variable current transfusion practices among academic pediatric institutions and in practice, 30% HbS may not be an easily attainable goal in this cohort of children with SCA and abnormal TCD. Children with sickle cell anemia (SCA) compose a high risk group for the development of stroke. If untreated, 11% will experience a clinical stroke by 20 years of age [2]. Adams et al. have shown that children with SCA who are at risk for primary stroke can be identified by measuring time-averaged mean blood flow velocities in the internal carotid or middle cerebral arteries by TCD [3]. Abnormal TCD velocities ( 200 cm/sec) are associated with high risk for stroke and warrant transfusion therapy to reduce the risk of primary stroke. First stroke can be successfully prevented in 90% of children with SCA and abnormal TCD velocities by the use of chronic transfusion therapy, with a goal of keeping HbS concentrations less than 30% [1]. TCD with Transfusions Changing to Hydroxyurea (TWiTCH) is an NHLBIsponsored, Phase III, multicenter trial comparing standard therapy (monthly transfusions) to alternative therapy (daily hydroxyurea) to reduce the risk of primary stroke in children with SCA and documented abnormal TCD velocities. Since transfusions compose the standard treatment arm, accurate %HbS values achieved in actual clinical practice were needed for protocol development. The majority of our information about transfusing patients with SCA to prevent stroke comes from secondary stroke prevention, i.e., the use of chronic red blood cell transfusions to prevent a second stroke after a first clinical stroke has occurred. Classically, transfusions are administered at 4-week intervals to maintain HbS at less than 30%. After several years of transfusion therapy, a few centers increase transfusion interval to 5–6 weeks and allow HbS to increase toward 50% in selected patients [4,5]. Our previous study in 295 children with SCA who received transfusions for secondary stroke prevention revealed an average pretransfusion HbS of 35 ± 11% with highly variable institutional %HbS levels ranging from 22 to 51% [6] In order to determine the current clinical standard of transfusion therapy for primary stroke prevention for elevated TCD velocities, we performed a larger survey of potential TWiTCH sites. We hypothesized that average pretransfusion HbS values achieved at pediatric academic centers would be higher than 30%. This study defines the current practice at academic medical centers in provision of chronic transfusion therapy to help reduce the risk of primary stroke in children with SCA. A total of 340 children with SCA and history of abnormal TCD velocities receiving chronic PRBC transfusions for primary stroke prophylaxis were identified at 32 institutions (Table I). The number of patients per site ranged from 3 to 33 (median 9 per site). A total of 3,970 transfusions were administered over the 12-month period, with a mean of 11.7 ± 2.8 transfusions per patient. Results were similar when analyzed by each patient contributing equally or each transfusion contributing equally (Table II). The predominant transfusion type by patient was defined as the technique used 6 times over the 12-month period. Most children (79%) received primarily simple transfusions, while 19% had primarily exchange transfusions (11% partial / manual exchange, 8% erythrocytapheresis), and 2% multiple transfusion types. The transfusion goal was <30% at almost all sites (84%), while at five sites, the %HbS was allowed in selected patients to increase to 50% after a period of clinical stability. The majority (95%) of the transfusions were administered within the defined 7-day window. On average, late transfusions were given 1.3 ± 5.5 days after the defined 7-day window. Thirty percent of the patients had at least one late transfusion and 14% had 2 or more late transfusions in the 1-year period. For the 3,653 transfusions with reported %HbS values (representing 92% of the 3,970 transfusions), the mean pretransfusion HbS percentage was 33.2 ± 14.0% (median 32%). The 75th percentile for HbS values was 41%, while the 90th percentile was 51%. There were substantial differences among institutional pretransfusion %HbS values, ranging from 23 ± 14% HbS at one institution where HbS was reported for 103 transfusions given to nine patients during the 12-month period, to 48 ± 15% at another institution where HbS was reported for 95 transfusions administered to nine patients during the same time frame (Table III). The five sites with increased HbS goals to 50% in selected patients did not have higher values than others. For each transfusion, subjects were less likely to have pretransfusion HbS <30% if they were older [OR 0.92 for each year increase in age, 95% CI (0.89, 0.96)] and on transfusions for a longer period of time [OR 0.90 for each year increase in duration, 95% CI (0.86, 0.94)]. Patients with higher pretransfusion Hb levels were more likely to have pretransfusion HbS <30% [OR 1.63 for each g/dL increase in Hb, 95% CI (1.46, 1.83)] and late transfusions were less likely to be associated with a pretransfusion HbS <30% [OR 0.27, 95% CI (0.18, 0.41)]. The Hb result does not appear to be a function of late transfusions since both covariates remained significant when modeled jointly. History of alloor autoantibodies, TCD velocity, and erythrocytapheresis use were not significant predictors of a pretransfusion HbS <30%. During the initial STOP study, transfusions were given to maintain pretransfusion HbS values at less than 30% [3]. However, there were frequent transient rises of HbS above this level [7]. Furthermore, extended follow-up results from the STOP study showed that pretransfusion %HbS values during the post-trial follow-up were higher than those during the STOP study [8]. The average %HbS per patient was 27.5 ± 12.4, still within the desired goal of 30%. However, pretransfusion HbS levels were 30–34.9% in 12%, 35–39.9% in 7%, and greater than 40% in 12% of the transfusions. In the STOP2 study, where children with abnormal TCD velocities whose Doppler readings became normal were randomly assigned to continue or stop transfusions, 24% of the patients had pretransfusion HbS levels greater than 30% [9]. These findings indicate that even in the context of a prospective clinical trial, maintaining HbS <30% was difficult to achieve. With the subsequent recommendation to treat all children with SCA who are at risk for primary stroke with transfusions to maintain HbS <30%, the feasibility of this approach in actual clinical practice is not known. Possible Letters

The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial.

In a phase‐II multi‐centre double‐blinded trial, we evaluated haematological effects of oral hydroxycarbamide (HC) and magnesium (Mg) in patients with HbSC, aged 5–53 years old. Subjects were randomized to HC + placebo, Mg + placebo, HC + Mg, or placebo + placebo. The primary endpoint was the proportion of hyperdense red blood cells after 8 weeks. Thirty‐six subjects were evaluable, but the study was terminated early because of slow enrollment. In the combined HC groups, mean cell volume and HbF were increased, but differences were not seen in hyperdense red cells or vaso‐occlusive events. Mg had no effects. Further investigation of hydroxycarbamide as monotherapy in HbSC disease is warranted.

SickleREMOTE: A two-way text messaging system for pediatric sickle cell disease patients

Sickle cell disease, the most common hemo-globinopathy in the world, affects patient lives from early childhood. Effective care of sickle cell disease requires frequent medical monitoring, such as tracking the frequency, severity, and duration of painful events. Conventional monitoring includes paper- or web-based reporting diaries. These systems require that patients carry forms, which are easily lost, or laptop computers, which are impractical to scale to large populations. Both are prone to sporadic use by older adolescents due to lack of reminders. In this paper, we design and prototype a Sickle cell disease REporting and MOnitoring TElemedicine system (SickleREMOTE), aiming to resolve limitations of conventional monitoring diaries. This monitoring system is configured as automated short message service text (SMS-text) messages that arrive at a mobile phone anywhere on a cellular network. The messages may be reminders to encourage treatment adherence or questionnaires to collect self-assessed clinical data relating to treatment adjustments. Patients respond to the messages using pre-determined templates and a cloud database parses and stores messages automatically. Providers use a web-based interface to view, analyze, and download collected data. SickleREMOTE is developed by Georgia Institute of Technology in conjunction with Childrens Healthcare of Atlanta (CHOA). System effectiveness will be evaluated using a trial of 30 adolescents with sickle cell disease and measured by response rate, time to response, error rate, and correspondence with data collected by telephone calls.

Using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning: results of a dose de-escalation trial.

High-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide. We conducted a multicenter dose de-escalation trial with the objective of decreasing the doses of busulfan and cyclophosphamide by 50% and 55%, respectively. Using day +28 donor-predominant chimerism as a surrogate endpoint for sustained engraftment, we completed the first 2 of 4 planned levels, enrolling 6 patients at each and reducing the total dose of cyclophosphamide from 200 mg/kg to 90 mg/kg. On the third level, which involved a reduction of i.v. busulfan from 12.8 mg/kg to 9.6 mg/kg, the first 2 patients had host-predominant T cell chimerism, which triggered trial-stopping rules. All 14 patients survive disease-free. No patients suffered severe regimen-related toxicity. Our results suggest BU-FLU-CY-ATG using lower dose CY could be a less toxic yet effective regimen. Further evaluation of this regimen in a full-scale clinical trial is warranted.

Activity and school attendance monitoring system for adolescents with Sickle cell disease

Sickle cell disease, the most common hemoglobin disorder, affects major organ systems with symptoms of pain, anemia and a multitude of chronic conditions. For adolescents, the disease adversely affects school attendance, academic progress and social activity. To effectively study the relationship among school attendance and other factors like demographics and academic performance, studies have relied on self-reporting and school records, all of which have some bias. In this study we design and prototype a system, called SickleSAM (Sickle cell School attendance and Activity Monitoring system), for automatically monitoring school attendance and daily activity of adolescents with sickle cell disease. SickleSAM intends to remove human bias and inaccuracies. The system uses built-in GPS to collect data which will be recorded into a cloud database using Short Messaging Service technology. SickleSAM is developed by Georgia Institute of Technology in conjunction with Childrens Healthcare of Atlanta (CHOA). System effectiveness is being evaluated using a trial of 10 adolescents with the disease.