Non-Myeloablative Conditioning and Bone Marrow Transplantation

NCT01850108 | Unknown Results DMC

• 1 other identifier: VICCNCCTT12108
• Study Type: interventional
• Target: 26
• Locations: 3 countries
• Sites: 3

Brief Summary

Allogeneic blood or marrow transplantation (alloBMT) is a curative therapy for a variety of hematologic disorders, including sickle cell disease and thalassemia. Even when it is clear that alloBMT can give to these patients an improvement in their disease, myeloablative transplants have important toxicities and mortalities associated. The lack of suitable donors continues to be a limit to access to transplantation. Substantial progress has been made recently in the development of pre-treatment regimens that facilitate the sustained engraftment of donor marrow with reduced toxicity. Most of these regimens incorporate highly immunosuppressive drugs, which allow the reduction or elimination of myeloablative agents or total body irradiation without endangering the sustained engraftment of HLA-identical allogeneic stem cells. Preliminary results of non-myeloablative allogeneic stem cell transplantation suggest that the procedure can be performed in patients who are ineligible for myeloablative alloBMT, and that sustained remissions of several hematologic malignancies can be obtained.

Conditions

Sickle Cell Disease; Hemoglobinopathies

Outcome Measures

Primary Outcomes (1)

• Transplant-related Mortality (TRM)

  Defined as death in the absence of recurrent sickle cell disease or hemoglobinopathy

  at 1 year after BMT

Secondary Outcomes (3)

• Number of Patients Who Developed Grade I-IV Acute Graft-vs.-Host Disease

  2 years

• Number of Patients With Donor Hematopoietic Chimerism in Peripheral Blood <95% at 6 Months After Mini-haploBMT

  Up to approximately 180 after mini-haploBMT

• Number of Participants With Hematologic and Non-hematologic Toxicities Following minihaploBMT

  Day 60 after BMT

Study Arms (1)

Non-Myeloablative Conditioning and Bone Marrow Transplantation

EXPERIMENTAL

Drug: Thymoglobulin; Drug: Fludarabine; Drug: Cyclophosphamide (CTX); Drug: Mesna; Drug: Sirolimus; Drug: Mycophenolate mofetil (MMF); Procedure: Bone marrow transplantation; Radiation: Total body irradiation

Interventions

Thymoglobulin DRUG

Day 9 before BMT: 0.5mg/kg IV; Days 8 \& 7 before BMT: 2mg/kg IV Days 8 \& 7 - 2mg/kg IV before BMT

Non-Myeloablative Conditioning and Bone Marrow Transplantation

Fludarabine DRUG

Days 6 and 2 before BMT: 30mg/m2/day IV

Also known as: Fludara®

Non-Myeloablative Conditioning and Bone Marrow Transplantation

Cyclophosphamide (CTX) DRUG

Days 6 and 5 before BMT: 14.5mg/kg IV; Days 3 and 4 after BMT: 50mg/kg/day

Also known as: Cytoxan

Non-Myeloablative Conditioning and Bone Marrow Transplantation

Mesna DRUG

Days 3 \& 4 after BMT: 40 mg/kg IV

Non-Myeloablative Conditioning and Bone Marrow Transplantation

Sirolimus DRUG

Adjusted to maintain a serum trough level of 3-12 ng/mL, taken orally beginning on 5 days after BMT and taken to 1 year after BMT.

Also known as: rapamycin, Rapamune®

Non-Myeloablative Conditioning and Bone Marrow Transplantation

Mycophenolate mofetil (MMF) DRUG

15 mg/kg orally with maximum dose 3 mg/day beginning 5 days after BMT and taken to day 35 after BMT

Non-Myeloablative Conditioning and Bone Marrow Transplantation

Bone marrow transplantation PROCEDURE

Day 0 - Transplantation of hematopoietic cells derived from bone marrow of a donor to a recipient as treatment for hematologic disorders

Non-Myeloablative Conditioning and Bone Marrow Transplantation

Total body irradiation RADIATION

200 cGy on the day before BMT. Radiation delivered to the entire body of the recipient to eradicate bone marrow cells in the recipient to prepare the recipient to receive the transplanted

Non-Myeloablative Conditioning and Bone Marrow Transplantation

Eligibility Criteria

• Age: 1 Year - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who are ineligible for BMT from an HLA-matched sibling donor can proceed to a haplo-BMT. Patients with an HLA-matched related donor will proceed to a matched BMT.
• Age 1-70 years
• Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100)
• Patients and donors must be able to sign consent forms. First degree relative should be willing to donate
• Patients must be geographically accessible and willing to participate in all stages of treatment.
• Eligible diagnoses: Patients with sickle cell anemia such as sickle cell anemia (Hb SS), Hb Sβ° thalassemia, Hb Sβ+thalassemia, Hb SC disease, Hb SE disease, Hb SD disease, Hemoglobin SO- Arab disease HbS with hereditary persistence of fetal hemoglobin. Other significant hemoglobinopathies.
• Plus one of the following:
• Attenuation of progressive disease (adults):
• Severe and debilitating vaso-occlusive pain despite hydroxyurea or regular blood transfusion therapy.
• Stroke and silent infarct; stroke or central nervous system event lasting more than 24 hours; MRI changes indicative of brain parenchyma damage and MRA evidence of cerebrovascular disease.
• Recurrent acute chest syndrome requiring exchange hospitalization.
• Chronic lung disease as defined by progressive restrictive disease irrespective of oxygen requirements.
• Chronic kidney disease, CKD stage II - IV
• Transfusion dépendent thalassemia

You may not qualify if:

• Poor performance status (ECOG\>1).
• Poor cardiac function: left ventricular ejection fraction\<35%.
• Poor pulmonary function: FEV1 and FVC\<40% predicted.
• Pulmonary hypertension moderate to severe by echocardiographic standards.
• Poor liver function: direct bilirubin \>3.1 mg/dl
• HIV-positive
• Minor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available.
• Prior transfusions from donor or recipient if caused alloimmunization vs. donor cells.
• Women of childbearing potential who currently are pregnant (Beta-HCG+) or who are not practicing adequate contraception.
• Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow-up. However, patients with history of stroke and significant cognitive deficit,that would preclude giving informed consent or assent will not be excluded, if they have a family member or significant other with Power of Attorney to also consent of their behalf.
• CRITERIA FOR DONOR ELIGIBILITY:
• Weight ≥ 20kg and age ≥ 18 years or per institutional guidelines
• Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) and will be screened per the American Association of Blood Banks (AABB). (AABB guidelines and the recipients will be informed of any deviations.)
• HLA-haploidentical first-degree relatives of the patient. Participants must be HLA typed at high resolution using DNA based typing at HLA-A, -B, -C and DRB1 and have available: An HLA haploidentical first degree relative donor (parents, siblings or half siblings, or children) with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required.
• When more than one donor is available, the donor with the lowest number of HLA allele mismatches will be chosen, unless there is HLA cross-match incompatibility or a medical reason to select otherwise, in which case donor selection is the responsibility of the PI, in consultation with the immunogenetics laboratory. In cases where there is more than one donor with the least degree of mismatch, donors will be selected based on the most favorable combination of:

Sponsors & Collaborators

• Vanderbilt-Ingram Cancer Center: lead

Study Sites (3)

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Saint-Louis Hospital

Paris, France

Location

St Mary's Hospital

London, United Kingdom

Location

Related Publications (2)

• Kassim AA, de la Fuente J, Nur E, Wilkerson KL, Alahmari AD, Seber A, Bonfim C, Simoes BP, Alzahrani M, Eckrich MJ, Horn B, Hanna R, Dhedin N, Rangarajan HG, Gouveia RV, Almohareb F, Aljurf M, Essa M, Alahmari B, Gatwood K, Connelly JA, Dovern E, Rodeghier M, DeBaun MR. An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease. Blood. 2024 Jun 20;143(25):2654-2665. doi: 10.1182/blood.2023023301.

  PMID: 38493482 DERIVED

• Aumann MA, Richerson W, Song AK, Davis LT, Pruthi S, Davis S, Patel NJ, Custer C, Kassim AA, DeBaun MR, Donahue MJ, Jordan LC. Cerebral hemodynamic changes after haploidentical hematopoietic stem cell transplant in adults with sickle cell disease. Blood Adv. 2024 Feb 13;8(3):608-619. doi: 10.1182/bloodadvances.2023010717.

  PMID: 37883803 DERIVED

Related Links

• Vanderbilt-Ingram Cancer Center, Find a Clinical Trial

MeSH Terms

Conditions

Anemia, Sickle Cell; Hemoglobinopathies

Interventions

thymoglobulin; fludarabine; fludarabine phosphate; Cyclophosphamide; Mesna; Sirolimus; Mycophenolic Acid; Bone Marrow Transplantation; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Tissue Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Radiotherapy; Investigative Techniques

Results Point of Contact

• Title: Teresa Melton
• Organization: Vanderbilt-Ingram Cancer Center

teresa.melton@vumc.org

615-936-7423

Study Officials

• Adetola A Kassim, MD

  Vanderbilt-Ingram Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine; Clinical Director, Sickle Cell Anemia Program; Medical Oncologist

Study Record Dates

• First Submitted: May 1, 2013
• First Posted: May 9, 2013
• Study Start: May 1, 2013
• Primary Completion: November 1, 2023
• Study Completion: December 31, 2024
• Last Updated: January 10, 2024
• Results First Posted: January 10, 2024

Record last verified: 2024-01

Locations

FR (1); GB (1); US (1)