Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Ninth Special Issue.

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. In the Ninth Edition, the JCA Special Issue Writing Committee has incorporated systematic review and evidence-based approaches in the grading of evidence and categorization of apheresis indications to make recommendations on the use of apheresis in a wide variety of diseases and conditions. This edition has largely maintained the general layout and concept of a fact sheet introduced in the Fourth Edition (2007). Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease or medical condition. The Ninth Edition of the JCA Special Issue comprises 91 fact sheets and 166 graded and categorized indications. This includes seven new fact sheets, nine new indications on existing fact sheets, and eight changes in the category for existing indications. The Ninth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.

Hematopoietic Stem Cell Transplantation in ARPC1B Deficiency.

Mutations in the ARPC1B isoform component of human actin-related protein 2/3 complex have been recently associated with an inborn error of immunity characterized by combined immunodeficiency, allergies, autoinflammation, and platelet abnormalities. Currently, indications on the management of this novel disease and information on its outcome are lacking. We report the first case series of 7 children with a homozygous mutation in ARPC1B gene who underwent allogeneic-HSCT (allo-HSCT). All patients presented an early clinical onset, characterized by recurrent infections, failure to thrive and gastrointestinal bleeding episodes complicated with neonatal hemorrhagic enteritis in 3 cases, and macrophage activating syndrome in 2. Allo-HSCT was performed at the median age of 1.83 years after a myeloablative conditioning regimen in all cases. Engraftment occurred in all patients with full donor chimerism in 6 out of 7. The clinical course after engraftment was uneventful in 3 out of 7 children; 2 patients developed a grade 1-2 acute graft-versus-host disease (GvHD), and 1 patient a grade 1 chronic-GvHD. JC virus-related progressive multifocal leukoencephalopathy was diagnosed in one patient 13 months after haploidentical-HSCT and successfully managed with donor-derived viral-specific T-cell infusion. Only one patient had a fatal outcome 3 months after HSCT because of sepsis, after veno-occlusive disease, and transplant-associated microangiopathy. At a median follow-up of 19 months (range 3-110), 6 out of 7 patients are alive and disease-free. The severity of the clinical phenotype at diagnosis and the high survival rate, with limited transplant-related morbidity, strongly support the indication to allo-HSCT for patients with this diagnosis.

Pre-transplant infusion of donor leukocytes treated with extracorporeal photochemotherapy induces immune hypo-responsiveness and long-term allograft survival in murine models.

Recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects. Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient's own blood cells. We sought to induce donor-specific hypo-responsiveness of SOT recipients by infusing ECP-treated donor leukocytes prior to transplant. To this end, we utilized major histocompatibility complex mismatched rodent models of allogeneic cardiac, liver, and kidney transplantation to test this novel strategy. Leukocytes isolated from donor-matched spleens for ECP treatment (ECP-DL) were infused into transplant recipients seven days prior to SOT. Pre-transplant infusion of ECP-DL without additional IS was associated with prolonged graft survival in all models. This innovative approach promoted the production of tolerogenic dendritic cells and regulatory T-cells with subsequent inhibition of T-cell priming and differentiation, along with a significant reduction of donor-specific T-cells in the spleen and grafts of treated animals. This new application of donor-type ECP-treated leukocytes provides insight into the mechanisms behind ECP-induced immunoregulation and holds significant promise in the prevention of graft rejection and reduction in need of global immune suppressive therapy in patients following SOT.

Considerations for immune effector cell therapy collections: a white paper from the American Society for Apheresis.

BACKGROUND AIMS: This white paper was developed to provide leukapheresis guidance for the collection of mononuclear cells from adult and pediatric patients who are destined for immune effector cell (IEC) therapies for commercial and research applications. Currently, there is considerable variability in leukapheresis processes and limited published information regarding best practices relevant to new cellular therapies, especially IECs. Herein the authors address critical leukapheresis questions in five domains to help guide consistent collection processes and ensure high-quality products. The first four domains are onboarding, pre-collection, collection and post-collection, with protocol feasibility, preparation, care and follow-up of the patient/donor at each step, respectively, and technical considerations during collection. The fifth domain of quality assurance focuses on ensuring product potency, purity, safety and auditing. METHODS: The American Society for Apheresis (ASFA) Clinical Applications Committee (IEC Therapy Subcommittee) was charged by the society's board of directors with working collaboratively with other ASFA committees and organizations, including the Foundation for the Accreditation of Cellular Therapy, Association for the Advancement of Blood and Biotherapies, American Society for Transplantation and Cellular Therapy, National Marrow Donor Program and International Society for Cell & Gene Therapy, to develop guidelines regarding leukapheresis collection of cells destined for the manufacture of IEC therapies. After a review of the literature and discussion with members of the involved committees and various institutions, a draft guidance was created and circulated for comment and revision. RESULTS: Critical aspects of apheresis that could affect the quality and quantity of the leukapheresis product were identified. These areas were then discussed and reviewed. After consensus, the best practice guidelines were proposed and accepted. CONCLUSIONS: In the current era of rapid growth of IEC therapies, it is important to address critical leukapheresis steps to provide high-quality products and more consistent practices and to eliminate redundant efforts.

Lack of defined apheresis collection criteria in publicly available CAR-T cell clinical trial descriptions: Comprehensive review of over 600 studies.

BACKGROUND: Chimeric antigen receptor T (CAR-T) cell successes have encouraged continued clinical study. Apheresis collection of starting material for CAR-T cell therapy product manufacturing is critical but described approaches suggest variability and clinical guidelines are currently lacking. The goal of this study was to gather and assess variability in apheresis collection descriptions in publicly available CAR T-cell therapy clinical trials. STUDY DESIGN: We searched clinicaltrials.gov (a publicly available clinical trial database) for "chimeric antigen receptor T cells" on July 01, 2020 and studies accessed July 30, 2020-August 15, 2020. Data collected included date posted, study characteristics, apheresis mentions (number, location, and context), laboratory parameters and transfusion allowances. Apheresis context was analyzed using a qualitative inductive approach of grounded theory method with open coding. Text was classified into 37 context codes, grouped into 12 categories, and then consolidated into patient, procedure, product, and miscellaneous themes. RESULTS: Apheresis was mentioned 1044 times in 322 (51.9%) of 621 total studies. Laboratory parameters mentioned included white blood cells (100 studies), absolute neutrophil count (220 studies), absolute lymphocyte count (102 studies), CD3+ cell (38 studies), hemoglobin (233 studies, 54 studies specified transfusion allowance), and platelet (269 studies, 48 studies specified transfusion allowance). CONCLUSIONS: Apheresis collection of CAR-T cell products is not well-defined in clinical study descriptions and the context is inconsistent. Laboratory parameters useful for apheresis collection are variably present and do not consistently align with current practices. Further exploration, and clinical guideline development will encourage alignment of apheresis collections for CAR-T cell products.

Betibeglogene Autotemcel Gene Therapy for Non-ß0/ß0 Genotype ß-Thalassemia.

BACKGROUND: Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent ß-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the ß-globin (ßA-T87Q) gene. METHODS: In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent ß-thalassemia and a non-ß0/ß0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). RESULTS: A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. CONCLUSIONS: Treatment with beti-cel resulted in a sustained HbAT87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-ß0/ß0 genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.).

Reduced-toxicity conditioning regimen with busulfan, fludarabine, rATG, and 400 cGy TBI in pediatric patients undergoing hematopoietic stem cell transplant for high-risk hematologic malignancies.

BACKGROUND: Myeloablative conditioning regimens decrease the risk of relapse in pediatric patients undergoing allogeneic hematopoietic stem cell transplant (HCT) for hematologic malignancies, but cause significant toxicities PROCEDURE: This prospective study evaluated the use of a reduced-toxicity, myeloablative regimen with dose-adjusted busulfan, fludarabine, antithymocyte globulin and 400 cGy of total body irradiation in 40 patients < 21 years of age undergoing HCT for high-risk leukemias. Busulfan pharmacokinetics were measured to target 4000 µmol*min/day in the first 30 patients; this was increased to 5000 µmol*min/day in the subsequent 10 in efforts to further decrease relapse risk RESULTS: Overall survival at two- and five-years post-HCT was 67% and 51%, respectively. Relapse occurred in 11 patients (28%) at a median of seven months and was the leading cause of death. Transplant-related mortality was 8% and 13% at 100 days and one-year post-HCT, respectively. Trends toward improved survival were seen in patients transplanted for myeloid disease using bone marrow as stem cell source who achieved a busulfan AUC > 4000 µmol*min/day with two-year relapse-free survival approaching 80% CONCLUSIONS: This conditioning regimen is safe and effective in patients with high-risk leukemias, particularly myeloid disease. Larger studies are needed to compare its safety and efficacy to other myeloablative regimens in this population.

A Novel Mutation in WAS Gene Causing a Phenotypic Presentation of Wiskott-Aldrich Syndrome: A Case Report.

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immunodeficiency, thrombocytopenia, and atopic dermatitis. OBSERVATIONS: This infant presented at birth with petechiae and bruising, with severe neonatal thrombocytopenia. Genetic testing for WAS revealed a variant of unknown significance hemizygous missense mutation in the WAS gene. This variant has not previously been reported. On the basis of the patient's clinical course including bleeding, infection, abnormal immune evaluation, and dermatologic sequelae, he was diagnosed with WAS and underwent allogeneic hematopoietic stem cell transplantation. CONCLUSIONS: We report a novel mutation in the WAS gene that causes a phenotypic presentation of Wiskott-Aldrich Syndrome.

Update to the ASFA guidelines on the use of therapeutic apheresis in ANCA-associated vasculitis.

Since 1986, the American Society for Apheresis (ASFA) has published practice guidelines on the use of therapeutic apheresis in the Journal of Clinical Apheresis (JCA) Special Issue. Since 2007, updated guidelines have been published every 3 years to reflect current evidence based apheresis practice with the most recent edition (8th) published in 2019. With each edition, the guidelines are reviewed and updated based on any newly published literature since the last review. The PEXIVAS study, an international, randomized controlled trial comparing therapeutic plasma exchange (TPE) vs no TPE and standard vs reduced dose steroid regimen on the primary composite outcome of end stage renal disease or death in patients with ANCA-associated vasculitis (AAV), was published in February 2020. This study represents the largest study on the role of therapeutic apheresis in AAV published to date and prompted the JCA Special Issue Writing Committee to reassess the current AAV fact sheet for updates based on this newly available evidence. This interim fact sheet summarizes current ASFA recommendations for the evidence-based use of therapeutic apheresis in AAV and supersedes the recommendations published in the 2019 guidelines.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue.

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.

American council on ECP (ACE): Why now?

Stimulated by the scientific progress in deciphering the principal elements contributing to the clinical efficacy of extracorporeal photochemotherapy (ECP), the American Council on ECP (ACE) was formed, under the auspices of the American Society for Apheresis (ASFA), to develop a field-guiding Consensus Report. ACE is composed of thirty nationally recognized ECP experts, clinically spanning cancer, transplantation, and autoimmunity and scientifically bridging immunology, bioengineering, and hematology. The two-day meeting took place in Manhattan, April 13-14, 2017, and unanimous consensus on nine pivotal points is herein reported. (1) ECP's clinical evolution must now enter a scientifically driven phase. (2) ECP is currently a bidirectional therapy, both immunizing and tolerizing simultaneously, via a single one-size-fits-all inflexible medical device. (3) To preclude inadvertent tolerization in the cancer setting, or immunization in the transplant rejection setting, polarization of ECP to either immunization or tolerization mode to match the clinical need is now possible and necessary. (4) Cutaneous T cell lymphoma (CTCL) is a genetically driven cancer, whose response to ECP is due to enhanced anti-cancer immunity. (5) ECP is a dendritic antigen-presenting cell (DC) based therapy. (6) ECP's efficacy can now be tested in a broad array of cancers. (7) ECP's capacity to tolerize to allotransplants via processing of donor leukocytes merits expedited human investigation. (8) UVA-8-MOP-impacted ECP-induced DC are potent antigen-specific tolerizing agents, while UVA-8-MOP(8-Methoxypsoralen)-spared ECP-induced DC are potent antigen-specific immunizing agents. (9) Six pilot clinical trial areas (CTCL, graft-vs.-host disease, ovarian carcinoma, anti-graft cytotoxic antibodies, pemphigus vulgaris, and haplotype mismatched stem cell transplants) are advised. ACE will be an ongoing advisory group for the field, with the goal of overseeing coordinated clinical and fundamental research efforts.

Fecal calprotectin and serum albumin as markers of gastrointestinal graft versus host disease.

BACKGROUND: Acute graft versus host disease (aGVHD) affects approximately 30-60% of patients after allogeneic hematopoietic stem cell transplantation (HCT) and our ability to predict who develops this complication and their response to treatment is limited. Fecal calprotectin has recently gained popularity as an effective marker of GI inflammation in patients with Inflammatory Bowel Disease (IBD). METHODS: Fecal calprotectin and albumin were evaluated as prognostic and predictive markers of aGVHD in 60 adult and pediatric HCT patients. Stool samples were sent for calprotectin quantification prior to starting conditioning, at day 14 post-HCT, at day 28 post-HCT, and at onset of aGVHD ±â€¯2 days. RESULTS: Fecal calprotectin did not differentiate patients with GI-GVHD and non-GI GVHD and did not vary based on severity. However, in patients with steroid-refractory GI aGVHD, significantly higher fecal calprotectin levels were noted. At onset of lower-GI symptoms, steroid refractory patients (n = 3) had a mean fecal calprotectin level of 449 ug/g (range 116-1111 ug/g) and a mean albumin of 1.93 g/dL (range 1.6-2.3 g/dL) compared with a mean fecal calprotectin of 24 ug/g (range 16-31 ug/g) and a mean albumin of 3.3 g/dL (range 2.3-3.9 g/dL) in steroid responsive patients (n = 9) (fecal calprotectin p = 0.032, albumin p = 0.027). CONCLUSION: Patients with steroid-refractory GI aGVHD had higher fecal calprotectin levels and lower albumin levels than patients with steroid-responsive disease. We recommend further studies to evaluate non-invasive tests with fecal calprotectin in combination with albumin in predicting steroid refractory disease at onset of symptoms to potentially identify patients that may benefit from upfront escalation in GVHD treatment.

Late Effects in Pediatric High-risk Neuroblastoma Survivors After Intensive Induction Chemotherapy Followed by Myeloablative Consolidation Chemotherapy and Triple Autologous Stem Cell Transplants.

Multimodal treatment in high-risk neuroblastoma has modestly improved survival; limited data exist on the late effects from these regimens. We report the sequelae of treatment incorporating 3 consecutive cycles of high-dose therapy and autologous stem cell transplants (ASCTs) without the use of total body irradiation (TBI). We reviewed the medical records of 61 patients treated on or following the Chicago Pilot 2 protocol between 1991 and 2008. Of the 25 patients who are alive (41%), 19 had near complete data to report. Specific treatment modalities and therapy-related side effects were collected. Fourteen of these 19 patients (74%) received 3 cycles of high-dose therapy with ASCT; follow-up occurred over a median of 13.9 years (range, 5.8 to 18.8 y). The majority of late effects were endocrine-related, including growth failure, hypothyroidism, and hypogonadism. Patients also developed secondary neoplasms and skeletal deformities. The most frequent sequela was hearing loss, seen in 17/19 patients. We found a high prevalence of various late effects in survivors of high-risk neuroblastoma using a non-TBI-based regimen including 3 cycles of high-dose therapy with ASCTs. As current treatment regimens recommend tandem ASCT without TBI, it is imperative that we understand and monitor for the sequelae from these modalities.

High-dose chemotherapy and autologous hematopoietic stem-cell rescue for treatment of relapsed and refractory Wilms tumor: Re-evaluating outcomes.

Wilms tumor (WT) treatment regimens are curative for more than 80% of patients, but those with relapsed or refractory disease continue to have poor outcomes. High-dose chemotherapy followed by autologous stem cell rescue is often utilized although outcomes remain variable. We report on HD-ASCR outcomes in 24 patients with relapsed or refractory Wilms tumor. Three-year disease free and overall survival are 46% and 60%, respectively, which is similar to those reported for conventional salvage therapies. These outcomes suggest that conventional salvage therapies should be employed for relapsed and refractory WT rather than HD-ASCR.

Extracorporeal photopheresis: cellular therapy for the treatment of acute and chronic graft-versus-host disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for many disease states. Despite significant improvements in strategies used to prevent and treat acute and chronic graft-versus-host disease (a/cGVHD), they continue to negatively affect outcomes of HSCT significantly. Standard, first-line treatment consists of corticosteroids; beyond this, there is little consistency in therapeutic regimens. Current options include the addition of various immunosuppressive agents, the use of which puts patients at even higher risks for infection and other morbidities. Extracorporeal photopheresis (ECP) is a widely used cellular therapy currently approved by the US Food and Drug Administration for use in patients with cutaneous T-cell lymphoma; it involves the removal of peripherally circulating white blood cells, addition of a light sensitizer, exposure to UV light, and return of the cells to the patient. This results in a series of events ultimately culminating in transition from an inflammatory state to that of tolerance, without global immunosuppression or known long-term adverse effects. Large-scale, prospective studies of the use of ECP in patients with a/cGVHD are necessary in order to develop the optimal treatment regimens.

Early mixed T-cell chimerism is predictive of pediatric AML or MDS relapse after hematopoietic stem cell transplant.

Patients with acute myeloid leukemia (AML) who relapse after hematopoietic stem cell transplantation (HCT) have dismal outcomes. Our ability to predict those at risk for relapse is limited. We examined chimerism trends post-HCT in 63 children who underwent HCT for AML or myelodysplastic syndrome (MDS). Mixed T-cell chimerism at engraftment and absence of chronic graft versus host disease (cGVHD) were associated with relapse (P = 0.04 and P = 0.02, respectively). Mixed T-cell chimerism at engraftment was predictive in patients without cGVHD (P = 0.03). Patients with engraftment mixed T-cell chimerism may warrant closer disease monitoring and consideration for early intervention.

Extracorporeal photopheresis in pediatric patients: Practical and technical considerations.

In adults, extracorporeal photopheresis (ECP) is widely utilized for a variety of indications, most commonly cutaneous T-cell lymphoma, acute or chronic graft-versus-host disease (GVHD), solid organ transplant rejection, and other autoimmune and T-cell-mediated disorders. In pediatric patients, the majority of case series and reports have focused on its use in the management of acute and chronic GVHD. Currently utilized ECP technologies were designed for adult patients and there are several challenges in adapting these technologies for use in children. In our review, we focus on practical considerations and procedural modifications for ECP use in pediatric patients, with special attention to patient safety.

Diagnostic Utility of Complement Immunohistochemical Studies in Post-Stem Cell Transplant Intestinal Thrombotic Microangiopathy: Case Report.

Thrombotic complications are a significant source of morbidity and mortality following hematopoietic stem cell transplants. Among them, transplant-associated thrombotic microangiopathy (TA-TMA) is a well-recognized syndrome that can affect various organ systems. Its etiology is related to endothelial injury accompanied by complement activation. As many of the signs and symptoms of the disease are also encountered in other complications following hematopoietic stem cell transplant, it can often be difficult to establish the diagnosis based on clinical data alone. Histopathologic examination of various tissues may be performed in difficult cases. However, the microscopic features of TA-TMA also overlap with those seen in other posttransplant complications, suggesting a need for additional tests to help in diagnosis. Here we describe a patient who presented with hemolytic anemia, thrombocytopenia, renal and neurological impairment, who also developed significant bloody diarrhea. Flexible sigmoidoscopy with biopsies was performed to determine the exact etiology of his gastrointestinal bleed. A diagnosis of intestinal TA-TMA was established with the use of immunohistochemical stains for complement components C5b-9 and C4d. This is the first report that highlights the utility of complement staining on histologic sections from digestive samples to render a definitive diagnosis of intestinal TA-TMA.

The Impact of High-resolution HLA-A, HLA-B, HLA-C, and HLA-DRB1 on Transplant-related Outcomes in Single-unit Umbilical Cord Blood Transplantation in Pediatric Patients.

Current practice for selecting donor units for umbilical cord blood transplant (UCBT) involves matching at HLA-A and HLA-B by low-resolution typing and the HLA-DRB1 allele by high-resolution (HR) typing. We retrospectively studied the impact of HR allele matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1 on transplant-related outcomes in 60 single-unit UCBTs in pediatric patients with malignant and nonmalignant conditions. Five-year overall survival of our cohort was 71% (95% confidence interval, 58-81); 27% experienced primary graft failure. Applying HR typing, donor-recipient mismatch variability increased ranging from 1/8 to 8/8, however, no impact on primary graft failure, graft-versus-host disease or posttransplant infection was observed. UCBTs with ≥6/8 HR matches did have a better overall survival (P=0.04) and decreased transplant-related mortality (P=0.02) compared with <6/8 HR matches. Using standard HLA typing, we showed an increased incidence of acute graft-versus-host disease (grade II to IV) and decreased transplant-related mortality in comparing the matched (6/6) versus ≤5/6 group (P=0.05 and 0.05, respectively). These data support the use of current guidelines for umbilical cord blood selection and encourage utilization of HR typing to select umbilical cord blood units matched at ≥6/8 especially when appropriate ≥5/6 units are available.