Allo HSCT for High Risk Hemoglobinopathies

Allogeneic Hematopoietic Stem Cell Transplant for Patients With High Risk Hemoglobinopathies and Other Red Cell Transfusion Dependent Disorders

A single center, open label, interventional, phase II trial for donor transplant for high risk hemoglobinopathies and other red cell transfusion dependent disorders utilizing allogeneic hematopoietic stem cell transplantation (HSCT) regimens.

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease; Hemoglobinopathies; Graft Failure
• Intervention / Treatment: Drug: Alemtuzumab; Radiation: Total Body Irradiation; Biological: Cell Infusion; Drug: Sirolimus; Drug: Mycophenolate Mofetil; Drug: Thymoglobulin; Drug: Fludarabine; Drug: Busulfan; Drug: Tacrolimus; Drug: Cyclophosphamide; Drug: Plerixafor (mozobil)

• Study Type: Interventional
• Enrollment (Estimated): 62
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ashish Gupta, MBBS, MPH; Phone Number: 612-626-2961; Email: gupta461@umn.edu

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • Masonic Cancer Center
      • Contact: Ashish Gupta, MBBS, MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Sickle Cell Disease (SCD)
• SCD Patients with a fully matched sibling donor (MSD) irrespective of the frequency or severity of symptoms MSD transplant can be considered. Parents/patient must be counseled as to the risks and benefits and provide their voluntary informed consent
• Transfusion Dependent Alpha- or Beta- Thalassemia
• Diamond Blackfan Anemia
• Other Non-Malignant Hematologic Disorders
• Karnofsky ≥ 60%, Lansky play score ≥ 60. Patients with lower performance score can be considered based on study team's evaluation.
• Sexually active persons of childbearing potential or persons with partners of childbearing potential must agree to use a highly effective form of contraception during study treatment and for at least 4 months after the transplant.

Exclusion Criteria:

• Pregnant, breastfeeding or intending to become pregnant during the study. Persons of childbearing potential must have a negative pregnancy test (serum or urine) within 30 days of the start of treatment
• HIV infection with a detectable viral load. All HIV+ patients must be evaluated by infectious disease (ID) and an HIV management plan established prior to transplantation.
• Active, uncontrolled infection - infection that is stable or improving after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections) will be permitted
• Known allergy to any of the study components
• Psychiatric illness/social situations that, in the judgement of the enrolling Investigator, would limit compliance with study requirements
• Other illness or a medical issue that, in the judgement of the enrolling Investigator, would exclude the patient from participating in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm B; Arm B Matched sib regimen - 0-55 (per physician preference for patients over 6) ATG/Flu/Bu	Biological: Cell Infusion; On day 0 the cells will be infused per cell source specific institutional guidelines; Drug: Mycophenolate Mofetil; MMF will begin on day -3 (Arm A, B & C) or day +5 (Arm D). Patients treated on adult service will receive 15 mg/kg (max 1500 mg/dose) given every 12 hours, rounded to nearest 250 mg. Patients on pediatric service will receive 15 mg/kg (max 1000 mg/dose) given every 8 hours. MMF dosing will be monitored and altered as clinically appropriate based on institutional guidelines. MMF will be stopped at day +30 (Arms A, B & C) or day +35 (Arm D) or 7 days after engraftment, whichever day is later, if no acute GVHD.; Other Names: (MMF); Drug: Thymoglobulin; ATG will be administered IV every 24 hours beginning on day -8 for all patients. Dosing will be model-based using Bayesian methodology13,14,15. Total doses and total number of doses (1-4 doses) will be determined based on absolute lymphocyte count and weight.; Other Names: Rabbit ATG; Drug: Fludarabine; Fludarabine will be administered IV over 1 hour every 24 hours on day -5 to day - 2. The daily dose of fludarabine will be determined by model-based dosing utilizing Bayesian methodology with a cumulative area under the curve (cAUC) of 20 mg*hr/L (range 18-22 mg*hr/L).; Drug: Busulfan; Busulfan dosing and administration and therapeutic drug monitoring (TDM) per institutional guidelines. Initial busulfan dosing will be determined by model-based dosing utilizing Bayesian methods with a cumulative area under the curve (cAUC) of 75 mg*hr/L.; Drug: Tacrolimus; Patients on Arm B and Arm C will receive tacrolimus, beginning on day -3 and continuing until day +180. Tacrolimus dosing and monitoring will be per institutional guidelines.
Experimental: Arm C; Arm C Fully Matched unrelated donor (MUD)- - 0-55 years; ATG/Flu/Bu	Biological: Cell Infusion; On day 0 the cells will be infused per cell source specific institutional guidelines; Drug: Mycophenolate Mofetil; MMF will begin on day -3 (Arm A, B & C) or day +5 (Arm D). Patients treated on adult service will receive 15 mg/kg (max 1500 mg/dose) given every 12 hours, rounded to nearest 250 mg. Patients on pediatric service will receive 15 mg/kg (max 1000 mg/dose) given every 8 hours. MMF dosing will be monitored and altered as clinically appropriate based on institutional guidelines. MMF will be stopped at day +30 (Arms A, B & C) or day +35 (Arm D) or 7 days after engraftment, whichever day is later, if no acute GVHD.; Other Names: (MMF); Drug: Thymoglobulin; ATG will be administered IV every 24 hours beginning on day -8 for all patients. Dosing will be model-based using Bayesian methodology13,14,15. Total doses and total number of doses (1-4 doses) will be determined based on absolute lymphocyte count and weight.; Other Names: Rabbit ATG; Drug: Fludarabine; Fludarabine will be administered IV over 1 hour every 24 hours on day -5 to day - 2. The daily dose of fludarabine will be determined by model-based dosing utilizing Bayesian methodology with a cumulative area under the curve (cAUC) of 20 mg*hr/L (range 18-22 mg*hr/L).; Drug: Busulfan; Busulfan dosing and administration and therapeutic drug monitoring (TDM) per institutional guidelines. Initial busulfan dosing will be determined by model-based dosing utilizing Bayesian methods with a cumulative area under the curve (cAUC) of 75 mg*hr/L.; Drug: Tacrolimus; Patients on Arm B and Arm C will receive tacrolimus, beginning on day -3 and continuing until day +180. Tacrolimus dosing and monitoring will be per institutional guidelines.; Drug: Plerixafor (mozobil); Plerixafor will beused to significantly increase stem cell yields on a second collection day compared to donors who continued mobilization on G-CSF only.
Experimental: Arm D; Arm D: Haploindentical or mismatched unrelated donors (MMUD) - 0-55 years; ATG/Thiotepa/Cyclophosphamide/MESNA/Flu/TBI	Drug: Sirolimus; Patients on Arm A and Arm D will receive sirolimus; beginning on day -3 and continuing until day +180 for patients on Arm A or beginning on day +5 and continuing until 1 year post transplant for patients on Arm D.; Drug: Tacrolimus; Patients on Arm B and Arm C will receive tacrolimus, beginning on day -3 and continuing until day +180. Tacrolimus dosing and monitoring will be per institutional guidelines.; Drug: Plerixafor (mozobil); Plerixafor will beused to significantly increase stem cell yields on a second collection day compared to donors who continued mobilization on G-CSF only.
Experimental: Arm A - Closed; Arm A Matched sib regimen - Age 6 -55 (per physician preference for patients over 6) Campath/TBI	Drug: Alemtuzumab; Alemtuzumab (Campath) will be administered IV over 2 hours on day -8 to day -4.; Other Names: Campath; Radiation: Total Body Irradiation; 400 cGy in 2 split fractions will be administered per Department of RadiationOncology SOPs.; Other Names: TBI; Biological: Cell Infusion; On day 0 the cells will be infused per cell source specific institutional guidelines; Drug: Sirolimus; Patients on Arm A and Arm D will receive sirolimus; beginning on day -3 and continuing until day +180 for patients on Arm A or beginning on day +5 and continuing until 1 year post transplant for patients on Arm D.; Drug: Mycophenolate Mofetil; MMF will begin on day -3 (Arm A, B & C) or day +5 (Arm D). Patients treated on adult service will receive 15 mg/kg (max 1500 mg/dose) given every 12 hours, rounded to nearest 250 mg. Patients on pediatric service will receive 15 mg/kg (max 1000 mg/dose) given every 8 hours. MMF dosing will be monitored and altered as clinically appropriate based on institutional guidelines. MMF will be stopped at day +30 (Arms A, B & C) or day +35 (Arm D) or 7 days after engraftment, whichever day is later, if no acute GVHD.; Other Names: (MMF)
Experimental: Arm E; Matched sib regimen - Age 6-55 (per physician preference for patients over 6) Campath/TBI with peripheral blood stem cell graft	Radiation: Total Body Irradiation; 400 cGy in 2 split fractions will be administered per Department of RadiationOncology SOPs.; Other Names: TBI; Biological: Cell Infusion; On day 0 the cells will be infused per cell source specific institutional guidelines; Drug: Sirolimus; Patients on Arm A and Arm D will receive sirolimus; beginning on day -3 and continuing until day +180 for patients on Arm A or beginning on day +5 and continuing until 1 year post transplant for patients on Arm D.; Drug: Mycophenolate Mofetil; MMF will begin on day -3 (Arm A, B & C) or day +5 (Arm D). Patients treated on adult service will receive 15 mg/kg (max 1500 mg/dose) given every 12 hours, rounded to nearest 250 mg. Patients on pediatric service will receive 15 mg/kg (max 1000 mg/dose) given every 8 hours. MMF dosing will be monitored and altered as clinically appropriate based on institutional guidelines. MMF will be stopped at day +30 (Arms A, B & C) or day +35 (Arm D) or 7 days after engraftment, whichever day is later, if no acute GVHD.; Other Names: (MMF); Drug: Thymoglobulin; ATG will be administered IV every 24 hours beginning on day -8 for all patients. Dosing will be model-based using Bayesian methodology13,14,15. Total doses and total number of doses (1-4 doses) will be determined based on absolute lymphocyte count and weight.; Other Names: Rabbit ATG; Drug: Fludarabine; Fludarabine will be administered IV over 1 hour every 24 hours on day -5 to day - 2. The daily dose of fludarabine will be determined by model-based dosing utilizing Bayesian methodology with a cumulative area under the curve (cAUC) of 20 mg*hr/L (range 18-22 mg*hr/L).; Drug: Tacrolimus; Patients on Arm B and Arm C will receive tacrolimus, beginning on day -3 and continuing until day +180. Tacrolimus dosing and monitoring will be per institutional guidelines.; Drug: Cyclophosphamide; Cyclophosphamide will be administered at a dose of 14.5 mg/kg over 2 hours IV daily on days -6 and -5. Cyclophosphamide dosing is calculated based on actual body weight (ABW). For Arm D - Cyclophosphamide 50 mg/kg IV will be administered over 2 hours on days +3 and +4. Cyclophosphamide dosing for post-transplant is calculated based on ideal body weight (IBW) unless patient weighs less than IBW, in which case actual body weight (ABW) will be used.; Other Names: Cyclophosphamide with MESNA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of Graft versus Host Disease (GvHD)	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival post HCT	1 and 2 years
Grade 3-4 Acute GvHD	Grade 3-4 acute Graft versus Host Disease (GvHD) at 2 years post HCT.	2 years
Chronic Graft versus Host Disease (GvHD) Free	Chronic Graft versus Host Disease (GvHD) Free at 2 years post HCT.	2 years
Failure Free Survival	Failure Free Survival 2 years post HCT.	2 years

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2024
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2032

Study Registration Dates

• First Submitted: March 5, 2025
• First Submitted That Met QC Criteria: March 6, 2025
• First Posted (Actual): March 12, 2025

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Hemoglobinopathies; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Investigative Techniques; Therapeutics; Fatty Acids; Lipids; Drug Therapy; Hydrocarbons, Acyclic; Hydrocarbons; Acids, Acyclic; Carboxylic Acids; Surgical Equipment; Equipment and Supplies; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Alkanes; Alcohols; Butylene Glycols; Glycols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Macrolides; Lactones; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Caproates; Sulfhydryl Compounds; Artificial Organs; Drug Delivery Systems; Infusion Pumps; Alemtuzumab; Sirolimus; Cyclophosphamide; Mycophenolic Acid; Tacrolimus; Mesna; Busulfan; fludarabine; Whole-Body Irradiation; plerixafor; thymoglobulin; Insulin Infusion Systems
• Other Study ID Numbers: 2024LS140

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No