ALBERT

Description: Measurement of cerebral blood velocity (CBV) by transcranial Doppler has been used to identify patients with sickle cell disease (SCD) who are at high risk of ischemic stroke. This study examines outcomes of bone marrow transplantation (BMT) and periodic blood transfusion (PBT) as a basis for making treatment recommendations for patients who have elevated CBV and no other indications for BMT. Decision analysis was used to compare the number of quality-adjusted life years (QALYs) experienced by a population of patients with SCD at high risk for stroke who were treated with PBT or BMT. Markov models were constructed to represent the clinical course of patients with SCD who were treated with PBT or BMT. Medical literature and expert opinion provided risks of stroke and death for different disease states, estimates of transition probabilities from one clinical state to another, and quality of life. An intention-to-treat analysis and an analysis of treatment received were both performed on hypothetical cohorts of 100 000 patients. Patients with SCD who were managed with a strategy of intending to provide BMT could expect 16.0 QALYs, compared with 15.7 QALYs for a strategy of intending to provide PBT; however, the variation around these estimates was large. In the treatment received analysis, patients compliant with PBT therapy and iron chelation could expect the best outcomes (19.2 QALYs). From a policy perspective, neither BMT nor PBT can be considered the “best” treatment for children with SCD who have abnormal CBV. Abnormal CBV should not be the only criterion for selecting patients with sickle cell for BMT.

Description: Alloimmunization to red cell antigens can seriously compromise the treatment of chronically transfused sickle cell patients by increasing the risk of delayed hemolytic transfusion reactions and decreasing the availability of suitable red cell units. In an effort to reduce the rate of alloimmunization, many institutions routinely provide transfusions that are phenotypically matched for selected red cell antigens. Controversy exists in this approach with some advocating the use of extensive matching protocols in which 9 or more red cell antigens are screened while others follow a more limited approach in which only 3–5 antigens are screened. Neither the relative clinical efficacy nor the cost-effectiveness of these approaches has been compared. In our institution a limited phenotype matching program was instituted in June 1999 in which red cells provided to all pediatric sickle cell patients are negative for C, E, and Kell antigens only. All patients are screened for the presence of red cell allo-antibodies prior to each transfusion and additional phenotype matching was performed for patients who develop specific antibodies other than C, E and/or Kell. We present here our experience with this limited phenotype matching approach in 169 pediatric sickle cell patients. The patients in our study have received a mean of 100.7 red cell transfusions (range 1–555). Overall, 36 (21.3%) patients developed at least one red cell alloantibody. However, 15 of these patients had developed antibodies to C, E, or Kell (or a combination) as a result of transfusion prior to referral to our hospital or as a result of transfusion here, prior to the routine implementation of our limited matching program. Therefore, only 21 patients (12.4%) developed red cell alloantibodies that could not be prevented by the consistent use of our protocol. These antibodies include; Jka (4), M (4), Fya (3), S (3), Cw (3), Lua (3), V (2), Jsa (2), and Lea, Leb, Kpa, Kna, Jkb, c (1 each). The rate of antibody production was 0.17/100 units transfused. Our results favorably compare with other reports of more extensive phenotypic matching programs (e.g, 6.7% of patients with red cell alloantibodies; 0.06 antibodies/100 units transfused). In addition, only 6 of our patients (3.6%) developed multiple (non-C, E, Kell) allo-antibodies. In 3 of these patients the antibodies developed were of questionable clinical significance (Lea, Leb, Kna) or would generally not be screened even in the most thorough phenotype matching program (Cw, Lua). Among our patients with multiple alloantibodies, compatible red cell units were easily available with 4–13% of ABO/Rh compatible units collected from a non-ethnically selected population being suitable. The extended screening carried out for this limited number of patients (3.6%) is a far more cost-effective and sustainable approach for a large sickle cell treatment program than would be possible with an extended phenotyping program including essentially all patients. It should be noted that none of our patients have demonstrated clinical evidence of either acute or delayed hemolysis. Finally, it is important to consider the relative cost-effectiveness of various phenotype matching protocols. At an approximate cost of $200 for each red cell unit and a fee of $85 for each additional antigen screened by our local blood supplier, each unit of red cells for our patients costs $455. In screening programs requiring more extensive matching (8–9 antigens screened) the cost per unit would be almost double this amount ($880–$965). Our study suggests that this limited antigen matching is effective in reducing alloimmunization in chronically transfused pediatric sickle cell patients and additionally does so in a more cost-effective manner than more extensive screening programs. Finally, even in those patients who ultimately developed red cell antibodies, the availability of suitable red cell products was never seriously compromised.

Description: Introduction: Transcranial Doppler ultrasonography (TCD) is an established screening modality used to predict stroke in children with sickle cell anemia (SCA). Children with abnormal TCD velocities are at high risk for primary stroke. Based on STOP and STOP 2 data, indefinite chronic red cell transfusion therapy is recommended for children with SCA and abnormal TCD velocity, defined as a maximum time-averaged mean velocity (TAMV) ≥200 cm/sec. The aim of the current analysis was to evaluate the long term effects of transfusion therapy on TCD velocities, in a large cohort of children with SCA who received chronic red cell transfusion therapy for primary stroke prophylaxis. Methods: The TCD With Transfusions Changing to Hydroxyurea (TWiTCH) study is a phase III, randomized, controlled, multicenter non-inferiority trial comparing hydroxyurea to transfusions for primary stroke prevention in children with SCA and abnormal TCD velocities (ClinicalTrials.gov NCT01425307). Children with SCA and a history of abnormal TCD who received at least 12 months of transfusion therapy were eligible to participate. All subjects’ index TCD velocities (the TCD examination that prompted the start of chronic transfusion therapy) were reviewed centrally to confirm study eligibility. At enrollment, study TCD velocities were obtained using the SONARA/tek TCD Module by trained examiners and reviewed centrally. In addition, all children were evaluated with brain magnetic resonance angiography (MRA) scans, which were also reviewed centrally. Associations between demographic, clinical, radiological, and laboratory findings and index/enrollment TCD velocities were examined. Results: One hundred and thirty eight children with complete data were included in this analysis. Mean age for the entire cohort at enrollment was 9.8±2.8 years; 40% were male and 98.8% had HbSS. Mean age at the diagnosis of index TCD was 5.5±2 years. The mean duration of transfusion therapy was 4.3±2.4 years with 63% receiving simple transfusions, 30% receiving partial exchange transfusions, and 7% undergoing erythrocytapheresis. The mean pre-transfusion hemoglobin at study entry was 9.1±0.8 gm/dL and the mean pre-transfusion %HbS for the last 6 months prior to study entry was 29.5±8.3%. The average index TCD TAMV was 217±22 cm/sec (range 147-325). At study entry, the average TAMV was lower at 150±27cm/sec overall (142±27 cm/sec on the left and 140±29 cm/sec on the right). In 77% of the subjects, the TCD velocities had decreased to normal levels (

Description: Key Points Children with SCA and stroke show severe parenchymal and vascular abnormalities that can be assessed using a vasculopathy grading scale. Results from the SWiTCH Trial support concerns about ineffectiveness of transfusion therapy in preventing cerebrovascular injury progression.

Description: Measurement of cerebral blood velocity (CBV) by transcranial Doppler has been used to identify patients with sickle cell disease (SCD) who are at high risk of ischemic stroke. This study examines outcomes of bone marrow transplantation (BMT) and periodic blood transfusion (PBT) as a basis for making treatment recommendations for patients who have elevated CBV and no other indications for BMT. Decision analysis was used to compare the number of quality-adjusted life years (QALYs) experienced by a population of patients with SCD at high risk for stroke who were treated with PBT or BMT. Markov models were constructed to represent the clinical course of patients with SCD who were treated with PBT or BMT. Medical literature and expert opinion provided risks of stroke and death for different disease states, estimates of transition probabilities from one clinical state to another, and quality of life. An intention-to-treat analysis and an analysis of treatment received were both performed on hypothetical cohorts of 100 000 patients. Patients with SCD who were managed with a strategy of intending to provide BMT could expect 16.0 QALYs, compared with 15.7 QALYs for a strategy of intending to provide PBT; however, the variation around these estimates was large. In the treatment received analysis, patients compliant with PBT therapy and iron chelation could expect the best outcomes (19.2 QALYs). From a policy perspective, neither BMT nor PBT can be considered the “best” treatment for children with SCD who have abnormal CBV. Abnormal CBV should not be the only criterion for selecting patients with sickle cell for BMT.

Description: Abstract 7 BABY HUG [Clinical Trials #NCT00006400], an NIH-NICHD sponsored randomized placebo-controlled trial showed that hydroxyurea (HU) administered to 9–18 month old children with sickle cell anemia (SCA) provides substantial clinical benefit. Benefits include a decrease in pain crises, acute chest syndrome events, need for transfusion and hospital admission; hematologic improvement include higher total and fetal hemoglobin concentration, larger red cell size, and lower WBC counts with toxicity limited to transient reduction in absolute neutrophil count (ANC) [Lancet 2011; 377:1663–72]. The parent or guardian of all 176 children who completed at least 18 months of randomized treatment were offered participation in an initial observational BABY HUG Follow-Up Study and 163 (93%) consented to participate. Clinical and laboratory data were collected every 6 months by structured abstraction of the medical record regarding use of clinically prescribed HU (dose escalation recommended), blood counts, clinical imaging, and sickle cell-related events. At the time of enrollment the family did not know their child's randomized study treatment assignment; 133 (82%) initially chose clinical prescription of open-label HU. Acceptance of HU has remained high through 36 months of follow-up; during each 6 month data collection period 68–75% of participants reported having taken HU. Only 2 patients have left the study (due to relocation) and more than 93% of expected data have been collected. Preliminary analyses as of May 2011, including 417 patient years (pt-yrs) of follow up, demonstrate that in comparison to participants not taking HU, children who continue to take HU have statistically lower rates of pain crises requiring emergency department (ED) visits, episodic transfusions, and hospital admissions for any reason, including acute chest syndrome or febrile illness (see table). The substantial decrease in acute chest syndrome episodes is similar to the effect demonstrated with HU use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of HU therapy in older children and adults. The decrease in the rate of admission for febrile events in HU-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain. There was no difference in hospitalization rates for painful events including dactylitis. Two patients in the non-HU group had a stroke. There were no differences between groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up children taking HU had persistently higher hemoglobin and MCV, and lower WBC and ANC than those not taking HU. Results of these analyses including growth and development assessments will enhance our understanding of the impact of HU use in children with SCA starting at a very young age. The accruing data from the BABY HUG Follow-Up Study demonstrate a continuation of the substantial benefits of early HU therapy with no discernable additional toxicities. Ongoing follow up of this cohort is essential to fully define these benefits as children grow, and to observe for late toxicity.Event Rate per 100 pt-yrsHUNo HUp valueED visit for Pain Crisis28.853.60.004Episodic Transfusion18.334.00.010Hospital Admission (any cause)74.9133.20.001Acute Chest Syndrome (admission)9.522.30.0001Febrile Illness (admission)30.764.3