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This is a single arm pilot study of peripheral stem cell transplantation (PSCT) with ex vivo t-cell receptor alpha beta+(TCRαβ+) T cell and cluster of differentiation 19+ beta (CD19+ B) cell depletion of unrelated donor (URD) grafts using the CliniMACS device in patients with sickle cell disease (SCD) and beta thalassemia major (BTM).
This is a single arm pilot study of peripheral stem cell transplantation (PSCT) with ex vivo TCRαβ+ T cell and CD19+ B cell depletion of URD grafts using the CliniMACS device in patients with SCD and BTM. Apart from CliniMACS-based cell processing, PSCT will be performed according to current standards of care in the Children's Hospital of Philadelphia (CHOP) Cell Therapy and Transplant Section, including the use of a standard chemotherapy conditioning regimen and standard follow-up laboratory assessments. The study will determine efficacy of this strategy in terms of engraftment, rates of acute and chronic Graft versus Host Disease (GvHD), and one-year overall and event-free survival.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sickle Cell Disease | Experimental | Patients with Sickle Cell Disease (SCD) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors. |
|
| Beta Thalassemias Major | Experimental | Patients with Beta Thalassemias Major (BTM) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CliniMACS | Device | Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of Graft Failure | Number of patients with primary graft failure (defined as no evidence of neutrophil engraftment by day +30 after stem cell infusion) and secondary graft failure (defined as ANC <500 for at least 7-10 days after initial engraftment occurs in the absence of known infection or drug-mediated suppression, and confirmed by hypocellular bone marrow biopsy and/or total donor chimerism percentage from blood or bone marrow < 10 percent) | Up to 1 year post-transplantation |
| Time to Neutrophil Engraftment | Number of days to neutrophil engraftment (first day of ANC >500/µl for the first of 3 consecutive days) | Up to 60 days post-transplantation |
| Incidence of Acute Graft vs. Host Disease (GVHD) | Acute GvHD was assessed by the number of patients who developed acute graft-versus-host disease, graded according to current Center for International Bone Marrow Transplant Registry (CIBMTR) reporting guidelines. Grading follows established criteria based on the severity of skin, liver, and gastrointestinal involvement, including extent of rash, bilirubin elevation, and gastrointestinal symptoms (e.g., diarrhea volume). Evaluation was performed by clinical assessment and laboratory data consistent with standard transplant-related acute GvHD grading practices. | Up to 100 days post-transplantation |
| Incidence of Chronic Graft vs. Host Disease (GVHD) | Number of patients with Grade II-IV acute GVHD, Severe Grade III-IV acute GVHD, and Chronic Extensive GVHD | Up to two years post-transplantation |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Deaths Due to Treatment | Number of subjects deaths that were related to study treatment | Up to 100 days post-transplantation |
| Probability of Event-free Survival (EFS) | Number of patients without complications or events |
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Inclusion criteria
Severe Sickle Cell Disease
Vaso-occlusive events include:
Beta Thalassemia Major
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Timothy Olson, MD, PhD | Children's Hospital of Philadelphia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28423290 | Background | Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med. 2017 Apr 20;376(16):1561-1573. doi: 10.1056/NEJMra1510865. No abstract available. | |
| 28104703 | Background | Maitra P, Caughey M, Robinson L, Desai PC, Jones S, Nouraie M, Gladwin MT, Hinderliter A, Cai J, Ataga KI. Risk factors for mortality in adult patients with sickle cell disease: a meta-analysis of studies in North America and Europe. Haematologica. 2017 Apr;102(4):626-636. doi: 10.3324/haematol.2016.153791. Epub 2017 Jan 19. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Sickle Cell Disease | Patients with Sickle Cell Disease (SCD) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors. CliniMACS: Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique |
| FG001 | Beta Thalassemias Major | Patients with Beta Thalassemias Major (BTM) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors. CliniMACS: Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sickle Cell Disease | Patients with Sickle Cell Disease (SCD) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors. CliniMACS: Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Rate of Graft Failure | Number of patients with primary graft failure (defined as no evidence of neutrophil engraftment by day +30 after stem cell infusion) and secondary graft failure (defined as ANC <500 for at least 7-10 days after initial engraftment occurs in the absence of known infection or drug-mediated suppression, and confirmed by hypocellular bone marrow biopsy and/or total donor chimerism percentage from blood or bone marrow < 10 percent) | Posted | Number | participants | Up to 1 year post-transplantation |
|
Subjects were followed up to 2 years post-transplantation
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sickle Cell Disease | Patients with Sickle Cell Disease (SCD) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors. CliniMACS: Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Secondary graft failure | Blood and lymphatic system disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Grade 2 acute graft vs host disease | Skin and subcutaneous tissue disorders | Przepiorka criteria | Non-systematic Assessment |
Our study is limited by a small sample size, and further multicenter analyses are necessary to firmly establish our conclusions.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Timothy Olson, MD PhD | Children's Hospital of Philadelphia | 215-590-2820 | cttsbmtintake@chop.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 25, 2022 | Jan 29, 2026 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 23, 2020 | Jan 29, 2026 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000755 | Anemia, Sickle Cell |
| D017086 | beta-Thalassemia |
| ID | Term |
|---|---|
| D000745 | Anemia, Hemolytic, Congenital |
| D000743 | Anemia, Hemolytic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
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|
| Up to 1 year post-transplantation |
| Probability of Overall Survival (OS) | Number of patients with the following survival outcome: one-year overall survival (OS) | 1 year post-transplantation |
| Incidence of Viral Reactivation and Symptomatic Viral Infection | Number of patients experiencing viral reactivation requiring therapy and symptomatic viral infections, including CMV, adenovirus, and EBV | Up to 1 year post-transplantation |
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| 7727769 | Background | Casper J, Camitta B, Truitt R, Baxter-Lowe LA, Bunin N, Lawton C, Murray K, Hunter J, Pietryga D, Garbrecht F, et al. Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia. Blood. 1995 May 1;85(9):2354-63. |
| 1873591 | Background | Ash RC, Horowitz MM, Gale RP, van Bekkum DW, Casper JT, Gordon-Smith EC, Henslee PJ, Kolb HJ, Lowenberg B, Masaoka T, et al. Bone marrow transplantation from related donors other than HLA-identical siblings: effect of T cell depletion. Bone Marrow Transplant. 1991 Jun;7(6):443-52. |
| 1571710 | Background | Bunin NJ, Casper JT, Lawton C, Murray K, Camitta BM, Greenwood M, Geil J, Ash RC. Allogeneic marrow transplantation using T cell depletion for patients with juvenile chronic myelogenous leukemia without HLA-identical siblings. Bone Marrow Transplant. 1992 Feb;9(2):119-22. |
| 12132044 | Background | Gordon PR, Leimig T, Mueller I, Babarin-Dorner A, Holladay MA, Houston J, Kerst G, Geiger T, Handgretinger R. A large-scale method for T cell depletion: towards graft engineering of mobilized peripheral blood stem cells. Bone Marrow Transplant. 2002 Jul;30(2):69-74. doi: 10.1038/sj.bmt.1703619. |
| 14985161 | Background | Barfield RC, Otto M, Houston J, Holladay M, Geiger T, Martin J, Leimig T, Gordon P, Chen X, Handgretinger R. A one-step large-scale method for T- and B-cell depletion of mobilized PBSC for allogeneic transplantation. Cytotherapy. 2004;6(1):1-6. doi: 10.1080/14653240310004411. |
| 12414722 | Background | Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol. 2003;21:139-76. doi: 10.1146/annurev.immunol.21.120601.141107. Epub 2002 Oct 16. |
| 17157172 | Background | Bethge WA, Haegele M, Faul C, Lang P, Schumm M, Bornhauser M, Handgretinger R, Kanz L. Haploidentical allogeneic hematopoietic cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity. Exp Hematol. 2006 Dec;34(12):1746-52. doi: 10.1016/j.exphem.2006.08.009. |
| 11477433 | Background | Handgretinger R, Klingebiel T, Lang P, Schumm M, Neu S, Geiselhart A, Bader P, Schlegel PG, Greil J, Stachel D, Herzog RJ, Niethammer D. Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant. 2001 Apr;27(8):777-83. doi: 10.1038/sj.bmt.1702996. |
| 17085305 | Background | Vodanovic-Jankovic S, Drobyski WR. Gammadelta T cells do not require fully functional cytotoxic pathways or the ability to recognize recipient alloantigens to prevent graft rejection. Biol Blood Marrow Transplant. 2006 Nov;12(11):1125-34. doi: 10.1016/j.bbmt.2006.08.033. |
| 10903774 | Background | Drobyski WR, Vodanovic-Jankovic S, Klein J. Adoptively transferred gamma delta T cells indirectly regulate murine graft-versus-host reactivity following donor leukocyte infusion therapy in mice. J Immunol. 2000 Aug 1;165(3):1634-40. doi: 10.4049/jimmunol.165.3.1634. |
| 10465102 | Background | Drobyski WR, Majewski D, Hanson G. Graft-facilitating doses of ex vivo activated gammadelta T cells do not cause lethal murine graft-vs.-host disease. Biol Blood Marrow Transplant. 1999;5(4):222-30. doi: 10.1053/bbmt.1999.v5.pm10465102. |
| 9028343 | Background | Drobyski WR, Majewski D. Donor gamma delta T lymphocytes promote allogeneic engraftment across the major histocompatibility barrier in mice. Blood. 1997 Feb 1;89(3):1100-9. |
| 12623838 | Background | Wilhelm M, Kunzmann V, Eckstein S, Reimer P, Weissinger F, Ruediger T, Tony HP. Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood. 2003 Jul 1;102(1):200-6. doi: 10.1182/blood-2002-12-3665. Epub 2003 Mar 6. |
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| 20539306 | Background | Bonneville M, O'Brien RL, Born WK. Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol. 2010 Jul;10(7):467-78. doi: 10.1038/nri2781. Epub 2010 Jun 11. |
| 17450185 | Background | Godder KT, Henslee-Downey PJ, Mehta J, Park BS, Chiang KY, Abhyankar S, Lamb LS. Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation. Bone Marrow Transplant. 2007 Jun;39(12):751-7. doi: 10.1038/sj.bmt.1705650. Epub 2007 Apr 23. |
| 17917892 | Background | Chaleff S, Otto M, Barfield RC, Leimig T, Iyengar R, Martin J, Holiday M, Houston J, Geiger T, Huppert V, Handgretinger R. A large-scale method for the selective depletion of alphabeta T lymphocytes from PBSC for allogeneic transplantation. Cytotherapy. 2007;9(8):746-54. doi: 10.1080/14653240701644000. Epub 2007 Oct 4. |
| 23993299 | Background | Schumm M, Lang P, Bethge W, Faul C, Feuchtinger T, Pfeiffer M, Vogel W, Huppert V, Handgretinger R. Depletion of T-cell receptor alpha/beta and CD19 positive cells from apheresis products with the CliniMACS device. Cytotherapy. 2013 Oct;15(10):1253-8. doi: 10.1016/j.jcyt.2013.05.014. |
| 28588018 | Background | Locatelli F, Merli P, Pagliara D, Li Pira G, Falco M, Pende D, Rondelli R, Lucarelli B, Brescia LP, Masetti R, Milano GM, Bertaina V, Algeri M, Pinto RM, Strocchio L, Meazza R, Grapulin L, Handgretinger R, Moretta A, Bertaina A, Moretta L. Outcome of children with acute leukemia given HLA-haploidentical HSCT after alphabeta T-cell and B-cell depletion. Blood. 2017 Aug 3;130(5):677-685. doi: 10.1182/blood-2017-04-779769. Epub 2017 Jun 6. |
| 24869942 | Background | Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo ME, Masetti R, Pende D, Falco M, Handgretinger R, Moretta F, Lucarelli B, Brescia LP, Li Pira G, Testi M, Cancrini C, Kabbara N, Carsetti R, Finocchi A, Moretta A, Moretta L, Locatelli F. HLA-haploidentical stem cell transplantation after removal of alphabeta+ T and B cells in children with nonmalignant disorders. Blood. 2014 Jul 31;124(5):822-6. doi: 10.1182/blood-2014-03-563817. Epub 2014 May 28. |
| BG001 | Beta Thalassemias Major | Patients with Beta Thalassemias Major (BTM) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors. CliniMACS: Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| HLA Donor Match Category (10/10 Matched vs 9/10 Mismatched) | Participants were categorized by donor-recipient HLA match status as either 10/10 matched or 9/10 mismatched. A 10/10 match was defined as allele-level concordance at HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1. A 9/10 mismatch indicated a single allele-level mismatch at any one of these loci. High-resolution DNA-based HLA typing was performed prior to infusion, and match status was determined at baseline using the donor-recipient pair as the unit of analysis. | Number | participants |
|
| OG001 | Beta Thalassemias Major | Patients with Beta Thalassemias Major (BTM) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors. CliniMACS: Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique |
|
|
| Primary | Time to Neutrophil Engraftment | Number of days to neutrophil engraftment (first day of ANC >500/µl for the first of 3 consecutive days) | Posted | Mean | Full Range | Days | Up to 60 days post-transplantation |
|
|
|
| Primary | Incidence of Acute Graft vs. Host Disease (GVHD) | Acute GvHD was assessed by the number of patients who developed acute graft-versus-host disease, graded according to current Center for International Bone Marrow Transplant Registry (CIBMTR) reporting guidelines. Grading follows established criteria based on the severity of skin, liver, and gastrointestinal involvement, including extent of rash, bilirubin elevation, and gastrointestinal symptoms (e.g., diarrhea volume). Evaluation was performed by clinical assessment and laboratory data consistent with standard transplant-related acute GvHD grading practices. | Posted | Number | participants | Up to 100 days post-transplantation |
|
|
|
| Primary | Incidence of Chronic Graft vs. Host Disease (GVHD) | Number of patients with Grade II-IV acute GVHD, Severe Grade III-IV acute GVHD, and Chronic Extensive GVHD | Posted | Number | participants | Up to two years post-transplantation |
|
|
|
| Secondary | Number of Deaths Due to Treatment | Number of subjects deaths that were related to study treatment | Posted | Number | participants | Up to 100 days post-transplantation |
|
|
|
| Secondary | Probability of Event-free Survival (EFS) | Number of patients without complications or events | Posted | Number | participants | Up to 1 year post-transplantation |
|
|
|
| Secondary | Probability of Overall Survival (OS) | Number of patients with the following survival outcome: one-year overall survival (OS) | Posted | Number | participants | 1 year post-transplantation |
|
|
|
| Secondary | Incidence of Viral Reactivation and Symptomatic Viral Infection | Number of patients experiencing viral reactivation requiring therapy and symptomatic viral infections, including CMV, adenovirus, and EBV | Posted | Number | participants | Up to 1 year post-transplantation |
|
|
|
| 1 |
| 7 |
| 2 |
| 7 |
| 7 |
| 7 |
| EG001 | Beta Thalassemias Major | Patients with Beta Thalassemias Major (BTM) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors. CliniMACS: Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique | 0 | 1 | 0 | 1 | 1 | 1 |
| Mild Chronic GVHD | Skin and subcutaneous tissue disorders | NIH consensus | Non-systematic Assessment |
|
| Grade 3 sinusoidal obstruction syndrome | Hepatobiliary disorders | CTCAE | Non-systematic Assessment |
|
| Grade 3 sepsis | Blood and lymphatic system disorders | CTCAE | Non-systematic Assessment |
|
| Grade 4 sepsis | Blood and lymphatic system disorders | CTCAE | Non-systematic Assessment |
|
| CMV reactivation | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| BK reactivation | Renal and urinary disorders | Non-systematic Assessment | Detected in blood and urine |
|
| Stroke | Nervous system disorders | CTCAE | Non-systematic Assessment | Grade 2, recurrent acute MCA stroke with no residual deficits |
|
Not provided
Not provided
| D006425 |
| Hemic and Lymphatic Diseases |
| D006453 | Hemoglobinopathies |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D013789 | Thalassemia |