Red Blood Cell - IMProving trAnsfusions for Chronically Transfused Recipients

Study Overview
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Brief Summary
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Red Blood Cell - IMProving trAnsfusions for Chronically Transfused recipients (RBC-IMPACT) is an observational cohort study to assess donor, component, and recipient factors that contribute to RBC efficacy in chronically and episodically transfused patients. The objective of the study is to determine how specific genetic and non-genetic factors in donors and recipients may impact RBC survival after transfusion - in short, what factors on both the donor and recipient side may improve the efficacy of the transfusion.

Detailed Description
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Sickle cell disease (SCD) and thalassemia are genetic disorders inducing anemia of differing pathophysiology. A primary therapy for preventing certain SCD complications (e.g., stroke) and for thalassemia major is regular red blood cell (RBC) transfusion, coupled with iron chelation to prevent the complications of transfusion-induced iron overload. For patients with pediatric hematology-oncology diagnoses with chemotherapy-induced aplasia, RBC transfusion is also common, but the degree of transfusion-induced iron overload and its implications for these patients is incompletely understood. Because iron-related tissue toxicity is a major cause of morbidity and mortality in regularly transfused patients, developing strategies to minimize iron loading and iron toxicity is a key objective of this proposal (study Aim #2), stemming from the objective to optimize RBC unit characteristics that patients with SCD and thalassemia receive beyond RBC phenotype matching for Rh C, E and K antigens (study Aim #1). The study will enroll patients with SCD, thalassemia or pediatric oncologic diagnoses receiving eligible transfusion at 6 hospital sites in the United States, as well as patients with SCD at 5 hemocenters in Brazil.

Official Title
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Red Blood Cell - IMProving trAnsfusions for Chronically Transfused Recipients (RBC-IMPACT)

Conditions
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Sickle Cell Disease, Thalassemia, Pediatric Cancer

Intervention / Treatment
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* Biological: Red Blood Cell (RBC) Transfusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Aim #1): Well-characterized transfusion-dependent form of SCD or thalassemia (including Hemoglobin E-thalassemia and sickle-beta thalassemia) on chronic simple transfusion therapy or partial manual exchange On a regular simple RBC transfusion schedule, including partial manual exchange (i.e., 1-3 units scheduled every 2-6 weeks and on a minimum 6-month chronic transfusion trial; for partial manual exchange, the phlebotomy must be completed before the transfusion is started without a back and forth between rounds of phlebotomy and transfusion) Seen at any participating domestic hub hospital (i.e., Columbia University Irving Medical Center/Morgan Stanley Children's Hospital of New York, Weill Cornell Medical Center/Komansky Children's Hospital, Boston Children's Hospital, Froedtert & Medical College of Wisconsin/Children's Wisconsin, University of California San Francisco, Benioff Children's Hospital Oakland) or enrolled in the Brazil REDS-IV-P sickle cell disease cohort and seen at any participating Brazil hemocenter (i.e., Childrens Institute and Adult Clinics at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - HCFMUSP, HEMOAM - Amazonas, HEMOMINAS - Minas Gerais, HEMOPE -Pernambuco, and HEMORIO - Rio de Janeiro) Exclusion Criteria (Aim #1): Institutionalization or imprisonment Foster care Weight <11 kg Inclusion criteria (Aim #2): Either included in Aim #1 (consented patient with SCD or thalassemia) or patient with pediatric oncologic diagnosis under care in a pediatric hematology/oncology service with anemia due to chemotherapy or primary/secondary hypo-proliferative bone marrow requiring a RBC transfusion (including HSCT) [In domestic study only] Age ≤21 years old (many pediatric services include care of patients up to age 21, therefore the protocol will not limit by age but instead on whether they are seen in a pediatric service) Planned transfusion of RBC from an aliquot or unit from a single donor Seen at any participating domestic hub hospital (i.e., Columbia University Irving Medical Center/Morgan Stanley Children's Hospital of New York, Weill Cornell Medical Center/Komansky Children's Hospital, Boston Children's Hospital, Froedtert & Medical College of Wisconsin/Children's Wisconsin, University of California San Francisco, Benioff Children's Hospital Oakland) or at any REDS-IV-P participating Brazil hemocenter (i.e., Childrens Institute and Adult Clinics at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - HCFMUSP, HEMOAM - Amazonas, HEMOMINAS - Minas Gerais, HEMOPE -Pernambuco, and HEMORIO - Rio de Janeiro). Exclusion criteria (Aim #2): Institutionalization or imprisonment Foster care Current active auto-immune hemolytic anemia based on positive direct antiglobulin test (DAT) with laboratory evidence of hemolysis and increased transfusion requirement [In domestic study only] Microangiopathic hemolytic anemia Weight <18 kg
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sickle cell disease (SCD)<br>Patients with SCD who are chronically transfused (in the U.S. and Brazil) | Biological: Red Blood Cell (RBC) Transfusion<br>* Simple RBC transfusion or partial manual exchange<br>|
| Thalassemia<br>Patients with thalassemia who are chronically transfused in the U.S. | Biological: Red Blood Cell (RBC) Transfusion<br>* Simple RBC transfusion or partial manual exchange<br>|
| Pediatric Hematology-Oncology<br>Patients in U.S. with pediatric oncologic diagnoses with hypo-proliferative bone marrow requiring single unit red blood cell transfusion | Biological: Red Blood Cell (RBC) Transfusion<br>* Simple RBC transfusion or partial manual exchange<br>|
| Blood Donors<br>Allogenic blood donors in the US (estimated: 10,200) and allogenic blood donors in Brazil (estimated: 2,100) with extended donation genotyping using an investigational hematology array. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hemoglobin A or Hemoglobin Level per day (RBC Survival) | Change in hemoglobin A or hemoglobin level per day in between subsequent transfusion episodes, for sickle cell disease and thalassemia cohorts, respectively | Baseline (immediately pre-) to post-transfusion over 2 years | 
| Change in Serum Iron Level | For all groups participating, change in serum iron measured from immediately prior to 2 hours post-transfusion | Baseline (immediately before) and 2-hours after transfusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin Increment | Hemoglobin increment [defined as Hb/HbA(post-transfusion)visit(i) - Hb/HbA(pre-transfusion)visit(i)] is associated with RBC survival | Baseline (immediately pre-) to post-transfusion, over 2 years | 
| Hemolysis Parameter Increment | Includes serum iron, indirect bilirubin, or plasma free hemoglobin | Baseline (immediately pre-) to post-transfusion or 2-hours post-transfusion, over 2 years | 
| Hepcidin Level | Hepcidin level at time of transfusion is a predictor of change in iron parameters (i.e., transferrin saturation, serum iron) following transfusion | Baseline (immediately before) to 2 hours after transfusion | 
| Non-Transferrin-Bound Iron (NTBI) Level | NTBI levels in patients with pediatric oncologic diagnoses with aplasia are elevated at baseline and increase following transfusion | Baseline (immediately before) to 2 hours after transfusion | 
| Number of Clinical Complications | Increased NTBI, serum iron, or transferrin saturation following transfusion is associated with increased risk of clinical adverse effects (i.e., new infections, SCD complications) | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle Cell Disease, Transfusion, Red Blood Cell, Thalassemia, Pediatric, Oncology, RBC survival, Genetic, Non-genetic, Observational, Blood donor